ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation

Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation
Literature review current through: Jan 2024.
This topic last updated: Apr 04, 2022.

INTRODUCTION — Allogeneic hematopoietic cell transplantation (HCT) is an important and potentially curative treatment option for a wide variety of malignant and nonmalignant diseases. Paradoxically, cytoreductive conditioning regimens designed to allow for successful allogeneic HCT are also detrimental to recovery of the immune system in general, and the production of lymphocytes in particular.

Delayed recovery of the immune system is associated with a high degree of morbidity and mortality [1-3]. Post-transplant immune depletion is particularly striking within the T cell compartment, which is exquisitely sensitive to negative regulation, evidenced by the profound decline in thymic function with age. As a consequence, regeneration of the immune system remains a significant unmet clinical need. Preclinical and clinical studies have revealed several promising therapeutic strategies to address ineffective lymphopoiesis and post-transplant immune deficiency.

Immune reconstitution following allogeneic HCT will be discussed here. Immunization following HCT and other supportive care issues surrounding HCT are presented separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients" and "Hematopoietic support after hematopoietic cell transplantation" and "Early complications of hematopoietic cell transplantation".)

The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). Otherwise, the source of such cells will be specified (eg, peripheral blood progenitor cell transplantation).

OVERVIEW OF IMMUNE RECONSTITUTION — A critical component of allogeneic HCT is the administration of chemotherapy and/or radiation therapy as a conditioning (or preparative) regimen with the goal of providing adequate immunosuppression to prevent rejection of the transplanted graft. Both alkylating chemotherapeutics and irradiation target highly proliferative cells [4-6], including developing and naïve lymphocytes [1]. As a result, following transplant, there is severe depletion of all hematopoietic cells of the immune system, especially lymphocytes. (See "Preparative regimens for hematopoietic cell transplantation".)

Recovery of the innate (natural) and adaptive immune systems occurs gradually during the post-transplantation period. Innate immunity usually recovers over the first several months. In comparison, reconstitution of adaptive immunity takes place over the first one to two years. As described in more detail below, the timing of immune reconstitution can be affected by many variables in the transplant process, such as the particular conditioning regimen, type of donor, source of hematopoietic progenitor cells, and approach to graft-versus-host disease (GVHD) prevention. (See 'Effect of transplant characteristics on immune reconstitution' below.)    

The following sections provide a general description of reconstitution of innate and adaptive immunity following transplant. A more detailed description of innate and adaptive immunity is presented separately. (See "An overview of the innate immune system" and "The adaptive humoral immune response" and "The adaptive cellular immune response: T cells and cytokines".)

Innate immunity — Innate (natural) immunity refers to immune responses that are present from birth and not learned, adapted, or permanently heightened as a result of exposure to microorganisms. The innate immunity is comprised of two fundamental components [7-9]:

The nonhematopoietic compartment, which includes physical barriers such as skin and mucosal surfaces

Hematopoietic cells including neutrophils, macrophages, as well as natural killer (NK) cells

While the nonhematopoietic components can be affected by the conditioning (preparative) regimens (eg, chemotherapy and/or radiation therapy) used in HCT, they are usually rapidly restored following HCT [10]. Importantly, repair of these physical barriers may be delayed by graft-versus-host disease if the skin and mucosal surfaces are involved. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Clinical and histological manifestations'.)

The first hematopoietic cells to engraft following HCT are monocytes, followed by granulocytes, platelets, and NK cells [10]. Neutrophil counts return to normal within two to four weeks; however, functionally they may remain suboptimal for up to four months [11]. While macrophages are not significantly depleted as a result of transplant conditioning, they are gradually replaced by donor-derived macrophages over the first several months after HCT [12]. Functionally, monocytes may remain suboptimal for up to one year [13,14]. NK cells recover both numerically and functionally within the first few weeks following HCT [15-17].

Adaptive immunity — Adaptive immunity is accomplished through B and T lymphocytes that are continually refined and adjusted throughout the lifetime of the individual. Following HCT, donor-derived T and B cell lymphocytes must reconstitute the cellular and humoral immune response systems.

The cellular immune response to pathogens is initiated by antigen presenting cells (eg, dendritic cells) and requires the activation of functional T cells. (See "The adaptive cellular immune response: T cells and cytokines".)

The humoral immune response is mediated by antibodies and requires both functional B cells (plasma cells, memory cells) and T cells. (See "The adaptive humoral immune response".)

Full recovery of these systems can take years to achieve, especially among patients with chronic graft-versus-host disease. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

Recovery of the adaptive cellular immune response — Following HCT, the adaptive immune system is significantly impaired largely due to the loss of naïve T cells and the reduced function of existing T cells [18-25]. There is a reversal of the CD4:CD8 ratio with low levels of CD4 positive T cells and normal or high levels of CD8 positive T cells [26].

Recovery of T cell immunity can occur via two independent routes [1,27]:

Peripheral expansion of infused donor memory T cells leading to a narrow T cell receptor repertoire

Seeding of the thymus by infused donor hematopoietic progenitors and subsequent generation of a diverse naïve T cell receptor repertoire

In patients receiving T cell replete grafts, peripheral expansion of infused memory T cells results in an initially narrow T cell receptor repertoire followed by expansion of the repertoire once seeding of the thymus generates naïve T cells. This latter mechanism becomes the predominant steady-state route of T cell development and is theoretically the only mechanism of T cell recovery in T cell depleted transplants. In contrast, the former mechanism would dominate in patients without a functional thymus.

As such, effective reconstitution of T cells following HCT requires a functional thymus, particularly in the case of CD4+ T cells [28]. This thymic-dependence in generating an effective T cell repertoire after HCT is a critical hurdle in aging patients, where thymic atrophy is common [29]. Compared with children, adults whose thymi have involuted are significantly impaired in their ability to recover following chemotherapy or HCT [18,24,27,30]. While both young and aged patients experience relatively rapid CD8+ T cell recovery [31], these CD8+ T cells are predominantly derived by clonal expansion that occurs outside the thymus [32,33]. Age-related thymic involution explains why full immune recovery is possible up until middle age, whereas in older patients the peripheral naïve T cell receptor repertoire is never fully restored [34] and infectious morbidity is directly related to low CD4 T cell counts [35]. (See 'Donor and recipient characteristics' below.)

Recovery of the humoral immune response — The humoral immune response is mediated by antibodies and requires both functional B cells (plasma cells, memory cells) and T cells. In addition to the delayed recovery of T cells described above, there is also significantly impaired reconstitution in cells of the B cell lineage following HCT [36,37]. In addition to resulting in an impaired response to pathogens, an impaired humoral immune response could, theoretically, lead to disease relapse or secondary malignancy [38-40].

Similar to T cells, B cell counts are completely depressed immediately after transplant, but reach normal levels by six months after autologous HCT and nine months after allogeneic HCT [41]. Much like the TCR repertoire, the B cell antibody repertoire is severely diminished and suffers a prolonged recovery [42]. Following allogeneic HCT, this diminished B cell reconstitution is predominantly due to graft-versus-host disease (GVHD) and to medications used to treat GVHD (particularly with high-dose corticosteroids and immunosuppressants) [43]. (See 'Graft-versus-host disease' below and "Treatment of chronic graft-versus-host disease".)

MEASUREMENT OF RECONSTITUTION — There is general consensus that immunoglobulin titers should be routinely measured after transplantation. We and others also believe that the CD4 count should be measured at one year following HCT as an assessment of overall adaptive immune function [44]. Of importance, the return of lymphocyte or immunoglobulin levels to normal numbers is not always indicative of normal immune function. (See "Laboratory evaluation of the immune system" and "Laboratory evaluation of the immune system", section on 'Advanced tests' and "Laboratory evaluation of the immune system", section on 'T cell function proliferation assays' and "Newborn screening for inborn errors of immunity", section on 'Overview of TREC screening test'.)

There is no ideal marker for the assessment of immune reconstitution. Clinical studies have used one or more of the following measures:

Overall and disease-free survival

Clinical or culture-proven infection

Absolute lymphocyte count

Absolute CD4 count

CD4/CD8 ratio

T cell subset testing by flow cytometry (eg, for CD45RA, a marker of naïve CD4+ T cells)

Immunoglobulin levels – Serum IgG levels

Rise in antigen specific antibody titer after vaccination

Advanced in vitro testing of B or T cell function, such as assay of mitogen-induced activation or quantification of T cell receptor rearrangement excision circles (TRECs), which correlate with newly formed antigen-specific T cells

T cell receptor spectratyping, which allows for assessment of receptor repertoire diversity

Deep sequencing of the T cell receptor to assess the T cell repertoire

Of these, perhaps the most reliable marker of humoral immune reconstitution is the documentation of a clinically significant rise in antigen-specific antibodies following vaccination or infection [44]. In addition, rising CD4 counts are associated with a lower risk of infection and improved outcomes in both HCT recipients and HIV positive populations. In one study, a CD4 T cell count <200/microL at three months was associated with increased infections, increased non-relapse mortality, and decreased overall survival [45]. Of importance, serum IgG levels may reflect either long-lived plasma cells that have survived the preparative regimen or B cell reconstitution [44].

EFFECT OF TRANSPLANT CHARACTERISTICS ON IMMUNE RECONSTITUTION — As described above, recovery of the innate and adaptive immune systems occurs gradually during the post-transplantation period. The timing of immune reconstitution can be affected by many variables in the transplant process, such as the source of stem cells, degree of human leukocyte antigen (HLA) and minor histocompatability antigen match, the conditioning regimen used and any manipulation the graft has had prior to transplant, immune suppressive therapy (especially corticosteroids), and the presence of graft-versus-host disease. Given the complexity of the transplant process, it is impossible to quantitate the impact of any one of these factors on an individual’s engraftment; all of these factors work in concert to affect immune reconstitution.

Donor and recipient characteristics — There are multiple options available in selecting a donor for an allogeneic HCT. The underlying disease, overall health of the donor and recipient, infectious history, clinical approach of the transplant center, and other factors are important in deciding what type of donor is selected. Importantly, characteristics of the donor, such as the degree of HLA-mismatch and donor age, may affect the timing of immune reconstitution.

HLA disparity – While most transplant centers prefer an HLA-matched sibling donor, it is estimated that these HLA-matched related donors are available in only approximately 25 percent of cases [46]. For patients without an HLA-matched sibling, HCT can be performed using a matched unrelated donor, a single antigen mismatched related donor, a matched or mismatched umbilical cord blood unit(s), or a haploidentical donor. When compared with HCT using alternative donors, HCT using an HLA-matched related donor offers the best chance of successful immune recovery [46,47]. Recipients of unrelated donor or non-HLA matched HCT have a higher rate of infectious complications than recipients of matched grafts [48-50]. However, emerging data from haploidentical HCT using post-transplant cyclophosphamide [51] or ex vivo T cell depletion with an TCRalpha/beta-specific antibody [52] have shown encouraging results regarding the pace of T cell reconstitution. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Donor age – Increasing donor age appears to be associated with an accumulating defect in hematopoietic stem cell function that skews the lineage potential away from lymphoid and toward myeloid precursors [53-56]. Moreover, hematopoietic stem cells from aged donors have been demonstrated experimentally to have reduced engraftment capacity and overall reconstitution potential [57-59]. Consequently, increased donor age, from as young as 36 years, can affect HCT outcomes [60-62]. (See "Donor selection for hematopoietic cell transplantation", section on 'Effect of donor characteristics'.)

Recipient age – Studies in mice and humans have demonstrated that, following total body irradiation and conditioning chemotherapy, there is significant damage to the thymic epithelial microenvironment resulting in reduced T cell development [63-71]. While previously thought to be relatively quiescent, the thymic microenvironment has been shown to be in a slow but constant flux, and to involute with age [72]. Recovery of thymic function following HCT is largely dependent upon the age of the recipient. In young patients, the long term recovery of thymic function is unaffected and the epithelial compartment eventually recovers from cytoreductive therapies [27,73]. In comparison, thymic damage caused by cytoreductive conditioning can be particularly detrimental in older individuals whose thymus has already undergone significant involution [74]. Although thymic aging can be observed as early as one year old [75], significant impacts on immune reconstitution are not readily apparent until after puberty [27,28,76]. This is discussed in more detail above. (See 'Recovery of the adaptive cellular immune response' above.)

Cytomegalovirus status – Cytomegalovirus (CMV)-positive recipients are at risk of CMV reactivation and increased transplant-related mortality post-HCT. CMV reactivation in this context is associated with the expansion of CMV-specific CD8-positive T effector memory cells and delays in the reconstitution of a more diverse T cell repertoire [77]. The risk of CMV reactivation post-HCT is discussed in more detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Risk of CMV'.)

Source of hematopoietic stem cells — There are several potential sources of hematopoietic stem cells used for HCT. The choice of stem cell source may affect immune reconstitution following HCT. Data regarding the impact of stem cell source on immune reconstitution largely come from retrospective studies and nonrandomized prospective trials.

Bone marrow – The bone marrow (BM) has traditionally been the source most frequently used in HCT. Following BM infusion, innate immunity usually recovers over the first several months. In comparison, reconstitution of adaptive immunity takes place over the first one to two years. This is described in more detail above. (See 'Overview of immune reconstitution' above.)  

Peripheral blood progenitor cells – Mobilized peripheral blood progenitor cells (PBPCs) have become a widely used stem cell source largely due to the convenience of peripheral collection. However, PBPC grafts contain approximately 1 log more T cells in the inoculum compared with BM [78], resulting in an increased risk of chronic graft-versus-host disease (GVHD) [79,80]. While homing of BM derived stem cells is slightly better than PBPCs [81], engraftment, as measured by platelet and neutrophil reconstitution, is significantly faster using PBPCs [80]. This is thought to be primarily due to the relatively small number of long-term reconstituting stem cells and large number of committed multipotent progenitors seen in PBPC grafts when compared with BM grafts [80]. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

Umbilical cord blood – Umbilical cord blood (UCB) is significantly enriched for hematopoietic stem cells and is used as an alternative stem cell source. One of the initial major obstacles to the widespread use of UCB for HCT was the limited quantity that can be collected from a single donor. This hurdle is at least partially overcome in adults by the transplantation of two unrelated, partially matched UCB grafts (double cord transplant) [82]. Following a double cord transplant, one of the grafts dominates long-term reconstitution while the other mediates short-term engraftment [83,84]. When compared with transplants of unrelated donor BM or mobilized PBPCs, UCB is associated with a longer median duration of neutropenia (approximately 30 versus 14 days), delayed acquired immune reconstitution, and more infectious-related morbidity [85-87]. However, there does not appear to be an increase in infection-related death. (See "Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens", section on 'Toxicity and transplant-related mortality'.)

Graft manipulation and cell dose — After collection, hematopoietic stem cell grafts are evaluated to determine the estimated stem cell dose. Some grafts also undergo T cell depletion or hematopoietic stem cell enrichment prior to infusion. The cell dose and graft manipulation can affect the speed of immune reconstitution following transplant.

Cell dose – The dose of hematopoietic stem cells infused affects the rates of hematopoietic recovery following HCT [88]. The dose required for rapid and stable long-term engraftment varies depending upon the method of measurement and the source of stem cells. This is discussed in more detail separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells" and "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Cell dose' and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

T cell depletion – Some centers use T cell depletion or hematopoietic stem cell enrichment to manipulate the stem cell graft in an effort to decrease rates of graft-versus-host disease (GVHD). While these techniques are effective in preventing acute GVHD across both major and minor histocompatibility barriers, removal of T cells from donor bone marrow may adversely affect engraftment, the adequacy of immune reconstitution, and the incidence of leukemic relapse or infections. T cell depletion of the allograft leads to significantly delayed immune reconstitution and causes increased morbidity and mortality from infection in both younger and older recipients [89-91]. Conversely, several small studies have demonstrated that a higher number of regulatory T cells (Tregs) in the graft is associated with improved immune reconstitution and reduced GVHD and cytomegalovirus infection [92-95]. (See "Prevention of graft-versus-host disease", section on 'In vivo TCD'.)

Conditioning and immunosuppression — The conditioning (or preparative) regimen is designed to provide adequate immunosuppression to prevent rejection of the transplanted graft. There are many different conditioning regimens that utilize chemotherapeutic drugs (eg, cyclophosphamide and busulfan) and/or total body irradiation [47]. Murine models have demonstrated that the use of higher intensity conditioning regimens can significantly enhance the engraftment of unrelated mismatched grafts, but also increase treatment-associated toxicity [96].

Conditioning regimens have been termed myeloablative, reduced intensity, and nonmyeloablative. While full agreement has not been achieved, definitions of these three types of conditioning regimens have been proposed. A myeloablative regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow and produce profound pancytopenia. The resulting pancytopenia is long-lasting, likely irreversible, and in most instances fatal, unless hematopoiesis is restored by infusion of hematopoietic stem cells. In comparison, host hematopoietic recovery is not fully eliminated following reduced intensity or nonmyeloablative conditioning. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Definitions'.)

As described above, the thymus is responsible for the generation of a diverse naïve T cell receptor repertoire. Following HCT, the thymus is seeded by infused donor hematopoietic progenitors, which are important for reconstituting the adaptive cellular immune response. While myeloablative, reduced intensity, and nonmyeloablative conditioning regimens can damage the thymus, it is not known whether the degree of thymic damage varies by conditioning intensity. The kinetics of immune reconstitution following nonmyeloablative conditioning have not been as well defined but suggest faster early recovery than with myeloablative conditioning, though with similar rate of recovery of late immune functions [10].

Also of considerable interest is the impact of conditioning regimens, both for HCT engraftment and for stem cell mobilization, on hematopoietic stem cell function. While quiescent hematopoietic stem cells are largely numerically spared from many chemotherapeutic and low-dose radiation regimes [97], their hematopoietic function appears to be significantly impaired [98,99]. Such cells appear to exhibit enhanced senescence coupled with an upregulation in the cyclin-depending kinase inhibitors p19Arf and p16ink4A [100,101], mimicking some of the effects seen with age.

Graft-versus-host disease — Immune reconstitution is significantly delayed by acute and chronic graft-versus-host disease (GVHD) and its therapy. The traditional description of chronic GVHD on the basis of time of onset (ie, after day 100 of HCT) has been replaced by emphasis on pathobiology [102]. Indeed, the clinical features consistent with chronic GVHD may be present as early as 50 days after HCT [102], and manifestations of acute GVHD may not develop until several months, particularly after nonmyeloablative conditioning, and may even overlap with the manifestations of chronic GVHD [103]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

GVHD can affect the skin and mucosal surfaces that comprise the nonhematopoietic compartment of the innate (natural) immune system. Damage to these areas from the conditioning regimen is usually rapidly reversed following HCT. However, repair of these physical barriers may be delayed by graft-versus-host disease if the skin and mucosal surfaces are involved.

Patients with chronic GVHD have significant defects in both humoral and cell-mediated immunity, delayed reconstitution of antigen presenting cells, and functional hyposplenism. Patients with acute GVHD can have lower plasma and dendritic cell nadir counts due to a graft-versus-host plasma cell/Langerhans cell effect [10,104]. Recovery of monocyte function can take up to one year, while the number and function of tissue dendritic cells (eg, Langerhans cells) can take up to six months. Immune reconstitution and response to vaccines can be further hindered by the use of systemic corticosteroids and other immunosuppressants to treat chronic GVHD [105]. In addition, the thymus has also been shown to be extremely sensitive to the treatments used to suppress the immune system from the impacts of GVHD, as well as GVHD itself [106-110].

THERAPEUTIC STRATEGIES TO IMPROVE IMMUNE RECONSTITUTION

Overview — A number of strategies have been proposed to enhance immune reconstitution following HCT. While many have been studied in preclinical settings, only a few have been translated to the clinic. Proposed strategies include the exogenous administration of cytokines and hormones (eg, keratinocyte growth factor, IL-7), sex steroid ablation (SSA), infusion of precursor lymphoid cells, and the creation of ectopic thymus tissue. Crosstalk between the thymic stroma and the hematopoietic compartment suggests that a combination of strategies targeting different compartments contributing towards thymopoiesis will lead to a greater regenerative boost than could be achieved with any single strategy alone. These strategies are described in the following sections.

Successful combinations are likely to be those that combine strategies targeting different pathways. As an example, it has been proposed that keratinocyte growth factor (KGF) may be successfully combined with precursor lymphocyte infusion [111], sex steroid ablation (SSA) [69], and temporary inhibition of p53 [70]. In contrast, it is unlikely that IL-7 could be used effectively in combination with KGF or SSA to promote thymopoiesis, as both of these strategies promote intrathymic production of IL-7, and studies in knockout mice demonstrate that both of these regenerative strategies are dependent on IL-7 [112,113].

Interaction between developing T cells and the supporting thymic stromal microenvironment is critical for normal thymus function, and has been exploited to great effect for thymic regeneration. However, the fundamental relationship between the bone marrow and the thymus, which is primarily predicated on the supply of lymphoid precursors, has been far less explored as a means for promoting immune regeneration. While the precise identity of the circulating progenitor released from the bone marrow to seed the thymus is unclear [114-118], the potential for improving immune reconstitution is not [119]. Fundamental defects in hematopoietic stem cell function, particularly in their ability to differentiate down the lymphoid lineage [120], may contribute towards some of the age-related changes observed in the thymus [121]. However, at least in studies of age-related thymic hypoplasia, improvement of stem cell function alone is not sufficient to restore thymopoiesis [122] and the reduced importation of progenitors is not enough to cause thymic involution [123]. This suggests that these defects in hematopoietic stem cell function merely contribute to, rather than cause, age-related declines in lymphopoiesis.

Cytokines and hormones — A number of strategies have been proposed to enhance immune reconstitution following HCT. While many have been studied in preclinical settings, only a few have been translated to the clinic. Proposed strategies have included the exogenous administration of cytokines and hormones identified by their ability to regenerate lymphopoiesis in model systems. Of these, keratinocyte growth factor (KGF), IL-7, Flt-3 ligand (Flt3L), and growth hormone (GH) have all shown promise in their regenerative abilities.

Keratinocyte growth factor – In animal models, exogenous administration of KGF has been found to increase thymic cellularity up to fourfold in the aged and following radiation or chemotherapy [112,124,125]. Furthermore, KGF can protect thymic epithelial cells (TECs) from graft-versus-host disease-mediated thymic damage [125], and KGF-induced thymopoiesis is mediated by proliferation and expansion of TECs [126]. While KGF has been approved by the US Food and Drug Administration for the prophylaxis of mucositis in recipients of high dose chemotherapy (including HCT), no clinical data exist regarding the potential of KGF to enhance T cell reconstitution in patients.

IL-7 – The pro-lymphopoietic cytokine IL-7 can act directly on T-lymphoid precursors and has been shown in several studies to enhance thymopoiesis. IL-7 appears to affect recent thymic emigrants and improve peripheral T cell function in aged mice and following allogeneic HCT in animal models [127-131]. IL7 appears to induce thymic regeneration by reversing age-related increases in apoptosis [132], while simultaneously enhancing the proliferation of lymphocytes and lymphoid precursors [127]. Administration of IL-7 in both animal models and humans has resulted in T cell proliferation, increased T cell numbers, and increased T cell receptor diversity [133]. A phase I trial of recombinant IL-7 in 12 adults undergoing T cell depleted allogeneic HCT suggested that this approach improved T cell recovery and T cell repertoire diversity without increased graft-versus-host disease or other toxicities [134].

Flt3L – Preclinical studies have shown that exogenous Flt3L enhances both thymic dependent and independent T cell reconstitution [135,136]. The effects of Flt3L are predominantly due to an expansion in Flt3+ progenitors in the bone marrow [137]. However, increases in T cell reconstitution can be at the expense of B-lymphopoiesis. Generation of B lymphocytes, in general, and early progenitors with lymphoid and myeloid potential, in particular, is significantly lower following the administration of exogenous Flt3L [138,139].

Growth hormone – Treatment with exogenous growth hormone (GH) regenerates the aged thymus [140,141] and enhances hematopoietic cell function in the bone marrow [142]. GH has also been shown to reverse irradiation-associated loss of bone marrow function determined by colony formation [142]. While the clinical experience with GH and T cell recovery is limited to studies in patients with HIV, it has been demonstrated to significantly enhance thymus function [143-145] and anti-viral responses in this population [143-146]. A phase 2 study testing the efficacy of growth hormone in combination metformin was reported showing a potential effect on thymus function, albeit in the absence of HCT (NCT04375657; [147]).

IL-22 – IL-22 has been identified as a prominent mediator of endogenous regeneration of thymic function after acute injury [148,149]. Administration of exogenous recombinant IL-22 has also been shown to improve thymopoiesis after acute thymic damage, such as caused by total body irradiation [148], and can promote thymopoiesis in the face of fulminant GVHD [150]. No clinical studies have reported the effect of IL-22 on immune reconstitution, but a phase 1-2 study (NCT02406651) to evaluate the efficacy of IL-22 to treat GVHD after allogeneic HCT will examine immune reconstitution.

BMP4 – BMP4 is produced by thymic endothelial cells, in response to damage to the thymus [151]. BMP4 enhances the ability of TECs to support differentiation of T cell precursors by stimulating the expression of the transcription factor FOXN1. Therapeutic administration of a cellular therapy based on thymic endothelial cells has shown promise in preclinical models of HCT and efforts are being made to translate this into clinical trials.

Several other cytokines and growth factors have been evaluated in this setting. IGF-1 promotes thymic endothelial cell expansion and enhances reconstitution following HCT [152-154]. IL-2 increases the number and function of regulatory T (Treg) cells and decreases clinical manifestations of chronic graft-versus-host disease among HCT recipients [155]. IL-15 predominantly promotes proliferation of circulating NK and T cells [156,157]. IL-12 stimulates thymic expression of IL-7 and enhances hematopoietic engraftment after transplant [158-160]. IL-15 and IL-12 have also been found to activate regulatory lymphoid-tissue inducer cells and NK cells [161,162]. Parathyroid hormone (PTH) can enhance hematopoietic stem cell numbers [163] and retinoic acid accelerates B lymphopoiesis [164]. RANKL, which has been reported to promote the steady-state differentiation of TEC subsets [165], can also promote T cell reconstitution when administered in mouse models of HCT [166].

Sex steroid ablation — Estrogen and testosterone have been implicated in the regulation of thymopoiesis [167,168], B-lymphopoiesis [169-171], and the generation of early lymphoid precursors [172,173]. Interest in the use of sex steroid ablation (SSA) to enhance immune reconstitution was initially born from animal studies that demonstrated improved thymic function following castration or chemical androgen blockade [174,175]. Subsequently, SSA has been investigated for its potential in enhancing the immune system following HCT.

Removal of sex steroids in aged mice and humans leads to reorganized thymic architecture and transport of circulating progenitors into the thymus [176], and subsequently enhances thymopoiesis [63,74,174-180]. The effects of SSA, however, are not restricted to the thymus and include enhanced B-lymphopoiesis and an increase in lymphoid progenitors [121,181-185], as well as enhanced overall immune recovery following autologous [186] and allogeneic [113] HCT, as well as cytoablative therapy [63,74,185].

Taken together, these studies suggest that SSA may improve immune reconstitution following HCT. As of yet, experimental and clinical data are largely limited to the use of luteinizing hormone releasing hormone (LHRH) analogues or surgical ablation. More advanced LHRH antagonists result in almost immediate cessation of sex steroid production and subsequently significantly shorter time to sex steroid ablation. Further study is warranted prior to its widespread application. Androgen deprivation is commonly employed in the treatment of patients with prostate cancer. Side effects of androgen deprivation are discussed in more detail separately. (See "Side effects of androgen deprivation therapy".)

Cellular therapies

Precursor lymphoid cells — Experimental studies suggest that lymphoid precursor cells can be isolated from donor bone marrow and infused into the recipient at the time of allogeneic HCT to boost T cell development following HCT [119]. These precursor T cell populations can be expanded using ex vivo culture systems that use Notch-1 stimulation of hematopoietic stem cells [111,187-189]. Importantly, precursor T cells can be transferred across major histocompatibility barriers and develop into host-tolerant and fully competent T cells [190].

In preclinical studies, adoptive transfer of T cell precursors into lethally irradiated allogeneic HCT recipients caused significant increases in thymic cellularity and chimerism, as well as enhanced peripheral T and NK cell reconstitution compared with recipients of allogeneic hematopoietic stem cells only [111,191,192]. In addition to the significant benefit for immune regeneration following transplant, in vitro generated pre-T cells can also be genetically engineered for tumor-specificity and subsequently used for targeted tumor immunotherapy [190]. A phase 1-2 study (NCT04959903) will test the effect of precursor T cells on immune reconstitution after allogeneic-HCT.

The use of donor lymphocyte infusions and other adoptive cell therapies as immunotherapy for the prevention and treatment of relapse (or infections) following HCT is presented separately. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

Artificial organs and bioreactors — Thymic tissue transplant has been used for the treatment of infants with congenital hypoplastic thymus (eg, DiGeorge syndrome), but is limited by the scarcity of thymic donor tissue. While efforts to create an ectopic thymus are underway, this approach is still in early phases of development. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis", section on 'Cultured thymic transplant'.)

Several groups are attempting to identify and isolate populations of thymic epithelial progenitor cells (TEPC) that could be used to directly enhance the function of the thymus by providing regenerative benefit to the supporting stromal microenvironment. While using different strategies, TEPC have been successfully isolated from fetal thymi and coaxed into generating a new thymus in FoxN1-/- recipients [193-196]; the identity and existence of a similar population in the adult thymus have thus far remained elusive [197,198]. However, one study has directed the reprogramming of thymic epithelial cells into functional multipotent skin stem cells [199]. A reverse of this approach, by reprogramming skin epithelium into TEPC, would offer an excellent opportunity to either regenerate the thymus by grafting TEPC directly or even ex vivo generation of a transplantable thymus.

There are also several approaches to rejuvenate immunity being considered that do not rely on the endogenous thymus at all, but rather concentrate on forming whole organs ex vivo that can be transplanted into patients as required [200,201]. One such approach removes the cells in an existing organ, leaving only the extracellular matrix components, and rebuilds the organ using biomatrices in addition to vascularizing chambers. Critically, this approach removes the significant immune barriers preventing xenogenic transplantation. This technique has so far been achieved in heart, liver, and lung [202-205].

Alternatively, an ectopic thymus might be generated ex vivo using TEPC and mesenchymal elements to seed biomatrices. One study, which used this approach in combination with implantable chambers that promote vascularization, was able to generate a functional thymus in vivo [206]. However, at this stage these approaches still require TEPC to initiate thymic organogenesis highlighting the dependence of fetal tissue and the importance of discovering an adult TEPC.

SUMMARY

Immune reconstitution after allogeneic hematopoietic cell transplantation (HCT) – Recovery of the innate (natural) and adaptive immune systems occurs gradually following allogeneic HCT. (See 'Overview of immune reconstitution' above.)

Other effects of HCT on immunity – Nonhematopoietic components of the innate immune system (eg, skin and mucosal linings) are damaged by the preparative regimen (eg, chemotherapy and/or radiation therapy), but are usually restored rapidly following HCT. Repair of these physical barriers may be delayed by graft-versus-host disease (GVHD) if the skin and mucosal surfaces are involved. (See 'Innate immunity' above.)

Recovery of innate immune function – Monocytes, granulocytes, and natural killer cells usually recover over the first several months after transplantation. Neutrophil counts return to normal within two to four weeks, but their function may be partially impaired for up to four months. Host-derived macrophages are gradually replaced by donor-derived macrophages over the first several months, and functionally may remain suboptimal for up to one year. Natural killer cells recover both numerically and functionally within the first weeks after transplant. (See 'Innate immunity' above.)

Recovery of adaptive immunity – Recovery of adaptive immunity usually takes one to two years, largely due to loss of naïve T cells, reduced function of existing T cells, and reversal of the CD4:CD8 ratio. Recovery of T cell immunity occurs via the peripheral expansion of infused donor memory T cells and/or seeding of the thymus by infused donor hematopoietic progenitors. B cell counts reach normal levels by nine months after HCT. Both the T cell receptor and B cell antibody repertoires are severely diminished and suffer prolonged recoveries. (See 'Adaptive immunity' above.)

Factors affecting recovery of immunity – The source of the graft, degree of immunologic match, conditioning regimen, manipulation of graft prior to transplant, and the presence of GVHD affect the pace of immune reconstitution. (See 'Effect of transplant characteristics on immune reconstitution' above.)

Strategies to improve immune recovery – Treatment with keratinocyte growth factor (KGF), IL-7, FLT-3 ligand (FLT3L), growth hormone (GH), and other agents are under active study to enhance immune recovery after allogeneic HCT. (See 'Therapeutic strategies to improve immune reconstitution' above.)

  1. Mackall CL, Fleisher TA, Brown MR, et al. Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood 1994; 84:2221.
  2. Pizzo PA, Rubin M, Freifeld A, Walsh TJ. The child with cancer and infection. II. Nonbacterial infections. J Pediatr 1991; 119:845.
  3. Mackall CL. T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review. Stem Cells 2000; 18:10.
  4. Brock N. The history of the oxazaphosphorine cytostatics. Cancer 1996; 78:542.
  5. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008; 8:59.
  6. Trobaugh FE Jr, Husseini S. Effects of radiation on hematopoietic tissue. Am J Med Technol 1973; 39:119.
  7. Bulek K, Swaidani S, Aronica M, Li X. Epithelium: the interplay between innate and Th2 immunity. Immunol Cell Biol 2010; 88:257.
  8. Metz-Boutigue MH, Shooshtarizadeh P, Prevost G, et al. Antimicrobial peptides present in mammalian skin and gut are multifunctional defence molecules. Curr Pharm Des 2010; 16:1024.
  9. Nochi T, Kiyono H. Innate immunity in the mucosal immune system. Curr Pharm Des 2006; 12:4203.
  10. Storek J, Geddes M, Khan F, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol 2008; 30:425.
  11. Zimmerli W, Zarth A, Gratwohl A, Speck B. Neutrophil function and pyogenic infections in bone marrow transplant recipients. Blood 1991; 77:393.
  12. Nakata K, Gotoh H, Watanabe J, et al. Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation. Blood 1999; 93:667.
  13. Cayeux S, Meuer S, Pezzutto A, et al. Allogeneic mixed lymphocyte reactions during a second round of ontogeny: normal accessory cells did not restore defective interleukin-2 (IL-2) synthesis in T cells but induced responsiveness to exogeneous IL-2. Blood 1989; 74:2278.
  14. Sahdev I, O'Reilly R, Black P, et al. Interleukin-1 production following T-cell-depleted and unmodified marrow grafts. Pediatr Hematol Oncol 1996; 13:55.
  15. Hokland M, Jacobsen N, Ellegaard J, Hokland P. Natural killer function following allogeneic bone marrow transplantation. Very early reemergence but strong dependence of cytomegalovirus infection. Transplantation 1988; 45:1080.
  16. Jacobs R, Stoll M, Stratmann G, et al. CD16- CD56+ natural killer cells after bone marrow transplantation. Blood 1992; 79:3239.
  17. Vitale C, Pitto A, Benvenuto F, et al. Phenotypic and functional analysis of the HLA-class I-specific inhibitory receptors of natural killer cells isolated from peripheral blood of patients undergoing bone marrow transplantation from matched unrelated donors. Hematol J 2000; 1:136.
  18. Weinberg K, Annett G, Kashyap A, et al. The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant 1995; 1:18.
  19. Roux E, Helg C, Dumont-Girard F, et al. Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts. Blood 1996; 87:3984.
  20. Dumont-Girard F, Roux E, van Lier RA, et al. Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood 1998; 92:4464.
  21. Ault KA, Antin JH, Ginsburg D, et al. Phenotype of recovering lymphoid cell populations after marrow transplantation. J Exp Med 1985; 161:1483.
  22. Gratama JW, Naipal A, Oljans P, et al. T lymphocyte repopulation and differentiation after bone marrow transplantation. Early shifts in the ratio between T4+ and T8+ T lymphocytes correlate with the occurrence of acute graft-versus-host disease. Blood 1984; 63:1416.
  23. Roosnek EE, Brouwer MC, Vossen JM, et al. The role of interleukin-2 in proliferative responses in vitro of T cells from patients after bone marrow transplantation. Evidence that minor defects can lead to in vitro unresponsiveness. Transplantation 1987; 43:855.
  24. Roux E, Dumont-Girard F, Starobinski M, et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 2000; 96:2299.
  25. Soiffer RJ, Bosserman L, Murray C, et al. Reconstitution of T-cell function after CD6-depleted allogeneic bone marrow transplantation. Blood 1990; 75:2076.
  26. Atkinson K, Hansen JA, Storb R, et al. T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets. Blood 1982; 59:1292.
  27. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332:143.
  28. Hakim FT, Memon SA, Cepeda R, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005; 115:930.
  29. Rodewald HR. The thymus in the age of retirement. Nature 1998; 396:630.
  30. Storek J, Witherspoon RP, Storb R. T cell reconstitution after bone marrow transplantation into adult patients does not resemble T cell development in early life. Bone Marrow Transplant 1995; 16:413.
  31. Mackall CL, Fleisher TA, Brown MR, et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 1997; 89:3700.
  32. Fagnoni FF, Lozza L, Zibera C, et al. T-cell dynamics after high-dose chemotherapy in adults: elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence. Immunology 2002; 106:27.
  33. Heitger A, Neu N, Kern H, et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90:850.
  34. Sfikakis PP, Gourgoulis GM, Moulopoulos LA, et al. Age-related thymic activity in adults following chemotherapy-induced lymphopenia. Eur J Clin Invest 2005; 35:380.
  35. Storek J, Gooley T, Witherspoon RP, et al. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 1997; 54:131.
  36. Storek J, Espino G, Dawson MA, et al. Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation. Blood 2000; 96:3290.
  37. Fry TJ, Mackall CL. Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future. Bone Marrow Transplant 2005; 35 Suppl 1:S53.
  38. MacLean GD, Reddish MA, Koganty RR, Longenecker BM. Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother Emphasis Tumor Immunol 1996; 19:59.
  39. von Mensdorff-Pouilly S, Verstraeten AA, Kenemans P, et al. Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol 2000; 18:574.
  40. White CA, Weaver RL, Grillo-López AJ. Antibody-targeted immunotherapy for treatment of malignancy. Annu Rev Med 2001; 52:125.
  41. Storek J. B-cell immunity after allogeneic hematopoietic cell transplantation. Cytotherapy 2002; 4:423.
  42. Li F, Jin F, Freitas A, et al. Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia in old mice. Eur J Immunol 2001; 31:500.
  43. Storek J, Wells D, Dawson MA, et al. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001; 98:489.
  44. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009; 15:1143.
  45. Kim DH, Sohn SK, Won DI, et al. Rapid helper T-cell recovery above 200 x 10 6/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37:1119.
  46. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 2010; 115:3861.
  47. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25:139.
  48. Hamza NS, Lisgaris M, Yadavalli G, et al. Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA-matched unrelated donor allogeneic transplantation in adults. Br J Haematol 2004; 124:488.
  49. van Kraaij MG, Verdonck LF, Rozenberg-Arska M, Dekker AW. Early infections in adults undergoing matched related and matched unrelated/mismatched donor stem cell transplantation: a comparison of incidence. Bone Marrow Transplant 2002; 30:303.
  50. Yoo JH, Lee DG, Choi SM, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004; 34:497.
  51. Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 2012; 39:683.
  52. Lang P, Teltschik HM, Feuchtinger T, et al. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol 2014; 165:688.
  53. Guerrettaz LM, Johnson SA, Cambier JC. Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging. Proc Natl Acad Sci U S A 2008; 105:11898.
  54. Muller-Sieburg CE, Cho RH, Karlsson L, et al. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood 2004; 103:4111.
  55. Signer RA, Montecino-Rodriguez E, Witte ON, et al. Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia. Blood 2007; 110:1831.
  56. Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 2005; 102:9194.
  57. Kamminga LM, van Os R, Ausema A, et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells 2005; 23:82.
  58. Kim M, Moon HB, Spangrude GJ. Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 2003; 996:195.
  59. Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 2005; 106:1479.
  60. Carreras E, Jiménez M, Gómez-García V, et al. Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 2006; 37:33.
  61. Harrison DE, Astle CM. Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 1982; 156:1767.
  62. Mehta J, Gordon LI, Tallman MS, et al. Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant 2006; 38:95.
  63. Goldberg GL, Dudakov JA, Reiseger JJ, et al. Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice. J Immunol 2010; 184:6014.
  64. Fredrickson GG, Basch RS. Early thymic regeneration after irradiation. Dev Comp Immunol 1994; 18:251.
  65. Hauri-Hohl MM, Zuklys S, Keller MP, et al. TGF-beta signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution. Blood 2008; 112:626.
  66. Popa I, Zubkova I, Medvedovic M, et al. Regeneration of the adult thymus is preceded by the expansion of K5+K8+ epithelial cell progenitors and by increased expression of Trp63, cMyc and Tcf3 transcription factors in the thymic stroma. Int Immunol 2007; 19:1249.
  67. Min D, Taylor PA, Panoskaltsis-Mortari A, et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 2002; 99:4592.
  68. Chung B, Barbara-Burnham L, Barsky L, Weinberg K. Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 2001; 98:1601.
  69. Kelly RM, Highfill SL, Panoskaltsis-Mortari A, et al. Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood 2008; 111:5734.
  70. Kelly RM, Goren EM, Taylor PA, et al. Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 2010; 115:1088.
  71. Williams KM, Mella H, Lucas PJ, et al. Single cell analysis of complex thymus stromal cell populations: rapid thymic epithelia preparation characterizes radiation injury. Clin Transl Sci 2009; 2:279.
  72. Gray DH, Seach N, Ueno T, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 2006; 108:3777.
  73. Sykes M, Szot GL, Swenson K, et al. Separate regulation of peripheral hematopoietic and thymic engraftment. Exp Hematol 1998; 26:457.
  74. Dudakov JA, Goldberg GL, Reiseger JJ, et al. Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J Immunol 2009; 183:7084.
  75. Flores KG, Li J, Sempowski GD, et al. Analysis of the human thymic perivascular space during aging. J Clin Invest 1999; 104:1031.
  76. Savage WJ, Bleesing JJ, Douek D, et al. Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism. Bone Marrow Transplant 2001; 28:463.
  77. Suessmuth Y, Mukherjee R, Watkins B, et al. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood 2015; 125:3835.
  78. Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97:3380.
  79. Russell NH, Gratwohl A, Schmitz N. Developments in allogeneic peripheral blood progenitor cell transplantation. Br J Haematol 1998; 103:594.
  80. Körbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001; 98:2900.
  81. Szilvassy SJ, Meyerrose TE, Ragland PL, Grimes B. Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood 2001; 98:2108.
  82. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105:1343.
  83. Avery S, Shi W, Lubin M, et al. Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood 2011; 117:3277.
  84. Gutman JA, Turtle CJ, Manley TJ, et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood 2010; 115:757.
  85. Delaney C, Gutman JA, Appelbaum FR. Cord blood transplantation for haematological malignancies: conditioning regimens, double cord transplant and infectious complications. Br J Haematol 2009; 147:207.
  86. Smith AR, Wagner JE. Alternative haematopoietic stem cell sources for transplantation: place of umbilical cord blood. Br J Haematol 2009; 147:246.
  87. Kanda J, Chiou LW, Szabolcs P, et al. Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:1664.
  88. Chen BJ, Cui X, Sempowski GD, et al. Hematopoietic stem cell dose correlates with the speed of immune reconstitution after stem cell transplantation. Blood 2004; 103:4344.
  89. Neven B, Leroy S, Decaluwe H, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood 2009; 113:4114.
  90. Cavazzana-Calvo M, Carlier F, Le Deist F, et al. Long-term T-cell reconstitution after hematopoietic stem-cell transplantation in primary T-cell-immunodeficient patients is associated with myeloid chimerism and possibly the primary disease phenotype. Blood 2007; 109:4575.
  91. Müller SM, Kohn T, Schulz AS, et al. Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)-identical and HLA-nonidentical stem cell transplantation. Blood 2000; 96:4344.
  92. Torelli GF, Lucarelli B, Iori AP, et al. The immune reconstitution after an allogeneic stem cell transplant correlates with the risk of graft-versus-host disease and cytomegalovirus infection. Leuk Res 2011; 35:1124.
  93. Rezvani K, Mielke S, Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 2006; 108:1291.
  94. Gaidot A, Landau DA, Martin GH, et al. Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention. Blood 2011; 117:2975.
  95. Winstead CJ, Reilly CS, Moon JJ, et al. CD4+CD25+Foxp3+ regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia. J Immunol 2010; 184:4749.
  96. Soderling CC, Song CW, Blazar BR, Vallera DA. A correlation between conditioning and engraftment in recipients of MHC-mismatched T cell-depleted murine bone marrow transplants. J Immunol 1985; 135:941.
  97. Gardner RV, McKinnon E, Astle CM. Analysis of the stem cell sparing properties of cyclophosphamide. Eur J Haematol 2001; 67:14.
  98. Gardner RV, McKinnon E, Poretta C, Leiva L. Hemopoietic function after use of IL-1 with chemotherapy or irradiation. J Immunol 2003; 171:1202.
  99. Meng A, Wang Y, Brown SA, et al. Ionizing radiation and busulfan inhibit murine bone marrow cell hematopoietic function via apoptosis-dependent and -independent mechanisms. Exp Hematol 2003; 31:1348.
  100. Meng A, Wang Y, Van Zant G, Zhou D. Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res 2003; 63:5414.
  101. Wang Y, Schulte BA, LaRue AC, et al. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 2006; 107:358.
  102. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11:945.
  103. Mielcarek M, Martin PJ, Leisenring W, et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102:756.
  104. Keever-Taylor. Immune reconstitution after allogeneic transplantation. In: Hematopoietic Stem Cell Transplantation, Soiffer RJ (Ed), Humana Press, Totowa, New Jersey 2008. p.377.
  105. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010; 24:257.
  106. Fletcher AL, Lowen TE, Sakkal S, et al. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J Immunol 2009; 183:823.
  107. Purton JF, Monk JA, Liddicoat DR, et al. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death. J Immunol 2004; 173:3816.
  108. Na IK, Lu SX, Yim NL, et al. The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. J Clin Invest 2010; 120:343.
  109. Krenger W, Holländer GA. The immunopathology of thymic GVHD. Semin Immunopathol 2008; 30:439.
  110. Krenger W, Rossi S, Holländer GA. Apoptosis of thymocytes during acute graft-versus-host disease is independent of glucocorticoids. Transplantation 2000; 69:2190.
  111. Zakrzewski JL, Kochman AA, Lu SX, et al. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 2006; 12:1039.
  112. Alpdogan O, Hubbard VM, Smith OM, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 2006; 107:2453.
  113. Goldberg GL, Alpdogan O, Muriglan SJ, et al. Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol 2007; 178:7473.
  114. Wada H, Masuda K, Satoh R, et al. Adult T-cell progenitors retain myeloid potential. Nature 2008; 452:768.
  115. Bell JJ, Bhandoola A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 2008; 452:764.
  116. Schwarz BA, Bhandoola A. Circulating hematopoietic progenitors with T lineage potential. Nat Immunol 2004; 5:953.
  117. Serwold T, Ehrlich LI, Weissman IL. Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis. Blood 2009; 113:807.
  118. Martin CH, Aifantis I, Scimone ML, et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat Immunol 2003; 4:866.
  119. Arber C, BitMansour A, Sparer TE, et al. Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation. Blood 2003; 102:421.
  120. Geiger H, Rudolph KL. Aging in the lympho-hematopoietic stem cell compartment. Trends Immunol 2009; 30:360.
  121. Dudakov JA, Khong DM, Boyd RL, Chidgey AP. Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution. Trends Immunol 2010; 31:191.
  122. Mackall CL, Gress RE. Thymic aging and T-cell regeneration. Immunol Rev 1997; 160:91.
  123. Gui J, Zhu X, Dohkan J, et al. The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol 2007; 19:1201.
  124. Min D, Panoskaltsis-Mortari A, Kuro-O M, et al. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007; 109:2529.
  125. Rossi S, Blazar BR, Farrell CL, et al. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 2002; 100:682.
  126. Rossi SW, Jeker LT, Ueno T, et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 2007; 109:3803.
  127. Alpdogan O, Muriglan SJ, Eng JM, et al. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest 2003; 112:1095.
  128. Lu H, Zhao Z, Kalina T, et al. Interleukin-7 improves reconstitution of antiviral CD4 T cells. Clin Immunol 2005; 114:30.
  129. Sempowski GD, Gooding ME, Liao HX, et al. T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol 2002; 38:841.
  130. Fry TJ, Moniuszko M, Creekmore S, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 2003; 101:2294.
  131. Chu YW, Memon SA, Sharrow SO, et al. Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function. Blood 2004; 104:1110.
  132. Andrew D, Aspinall R. Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol 2001; 166:1524.
  133. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11:330.
  134. Perales MA, Goldberg JD, Yuan J, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood 2012; 120:4882.
  135. Fry TJ, Sinha M, Milliron M, et al. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 2004; 104:2794.
  136. Kenins L, Gill JW, Boyd RL, et al. Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation. J Exp Med 2008; 205:523.
  137. Wils EJ, Braakman E, Verjans GM, et al. Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J Immunol 2007; 178:3551.
  138. Balciunaite G, Ceredig R, Massa S, Rolink AG. A B220+ CD117+ CD19- hematopoietic progenitor with potent lymphoid and myeloid developmental potential. Eur J Immunol 2005; 35:2019.
  139. Ceredig R, Rauch M, Balciunaite G, Rolink AG. Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment. Blood 2006; 108:1216.
  140. Dixit VD, Yang H, Sun Y, et al. Ghrelin promotes thymopoiesis during aging. J Clin Invest 2007; 117:2778.
  141. Taub DD, Longo DL. Insights into thymic aging and regeneration. Immunol Rev 2005; 205:72.
  142. Carlo-Stella C, Di Nicola M, Milani R, et al. Age- and irradiation-associated loss of bone marrow hematopoietic function in mice is reversed by recombinant human growth hormone. Exp Hematol 2004; 32:171.
  143. Herasimtschuk AA, Westrop SJ, Moyle GJ, et al. Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up. J Immune Based Ther Vaccines 2008; 6:7.
  144. Napolitano LA, Schmidt D, Gotway MB, et al. Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 2008; 118:1085.
  145. Napolitano LA, Lo JC, Gotway MB, et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 2002; 16:1103.
  146. Plana M, Garcia F, Darwich L, et al. The reconstitution of the thymus in immunosuppressed individuals restores CD4-specific cellular and humoral immune responses. Immunology 2011; 133:318.
  147. Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 2019; 18:e13028.
  148. Dudakov JA, Hanash AM, Jenq RR, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 2012; 336:91.
  149. Pan B, Liu J, Zhang Y, et al. Acute ablation of DP thymocytes induces up-regulation of IL-22 and Foxn1 in TECs. Clin Immunol 2014; 150:101.
  150. Dudakov JA, Mertelsmann AM, O'Connor MH, et al. Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood 2017; 130:933.
  151. Wertheimer T, Velardi E, Tsai J, et al. Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci Immunol 2018; 3.
  152. Alpdogan O, Muriglan SJ, Kappel BJ, et al. Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation. Transplantation 2003; 75:1977.
  153. Chu YW, Schmitz S, Choudhury B, et al. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 2008; 112:2836.
  154. Taguchi T, Takenouchi H, Matsui J, et al. Involvement of insulin-like growth factor-I and insulin-like growth factor binding proteins in pro-B-cell development. Exp Hematol 2006; 34:508.
  155. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365:2055.
  156. Alpdogan O, Eng JM, Muriglan SJ, et al. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood 2005; 105:865.
  157. Alpdogan O, van den Brink MR. IL-7 and IL-15: therapeutic cytokines for immunodeficiency. Trends Immunol 2005; 26:56.
  158. Chen J, Wang J, Li J, et al. Enhancement of cytotoxic T-lymphocyte response in aged mice by a novel treatment with recombinant AdIL-12 and wild-type adenovirus in rapid succession. Mol Ther 2008; 16:1500.
  159. Chen T, Burke KA, Zhan Y, et al. IL-12 facilitates both the recovery of endogenous hematopoiesis and the engraftment of stem cells after ionizing radiation. Exp Hematol 2007; 35:203.
  160. Li L, Hsu HC, Stockard CR, et al. IL-12 inhibits thymic involution by enhancing IL-7- and IL-2-induced thymocyte proliferation. J Immunol 2004; 172:2909.
  161. Eisenring M, vom Berg J, Kristiansen G, et al. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol 2010; 11:1030.
  162. Satoh-Takayama N, Lesjean-Pottier S, Vieira P, et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J Exp Med 2010; 207:273.
  163. Adams GB, Martin RP, Alley IR, et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol 2007; 25:238.
  164. Chen X, Esplin BL, Garrett KP, et al. Retinoids accelerate B lineage lymphoid differentiation. J Immunol 2008; 180:138.
  165. Nitta T, Ohigashi I, Nakagawa Y, Takahama Y. Cytokine crosstalk for thymic medulla formation. Curr Opin Immunol 2011; 23:190.
  166. Lopes N, Vachon H, Marie J, Irla M. Administration of RANKL boosts thymic regeneration upon bone marrow transplantation. EMBO Mol Med 2017; 9:835.
  167. Olsen NJ, Kovacs WJ. Effects of androgens on T and B lymphocyte development. Immunol Res 2001; 23:281.
  168. Zoller AL, Kersh GJ. Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes. J Immunol 2006; 176:7371.
  169. Grimaldi CM, Jeganathan V, Diamond B. Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J Immunol 2006; 176:2703.
  170. Kincade PW, Medina KL, Payne KJ, et al. Early B-lymphocyte precursors and their regulation by sex steroids. Immunol Rev 2000; 175:128.
  171. Viselli SM, Reese KR, Fan J, et al. Androgens alter B cell development in normal male mice. Cell Immunol 1997; 182:99.
  172. Igarashi H, Kouro T, Yokota T, et al. Age and stage dependency of estrogen receptor expression by lymphocyte precursors. Proc Natl Acad Sci U S A 2001; 98:15131.
  173. Medina KL, Garrett KP, Thompson LF, et al. Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen. Nat Immunol 2001; 2:718.
  174. Heng TS, Goldberg GL, Gray DH, et al. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 2005; 175:2982.
  175. Sutherland JS, Goldberg GL, Hammett MV, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005; 175:2741.
  176. Williams KM, Lucas PJ, Bare CV, et al. CCL25 increases thymopoiesis after androgen withdrawal. Blood 2008; 112:3255.
  177. Greenstein BD, Fitzpatrick FT, Kendall MD, Wheeler MJ. Regeneration of the thymus in old male rats treated with a stable analogue of LHRH. J Endocrinol 1987; 112:345.
  178. Olsen NJ, Watson MB, Henderson GS, Kovacs WJ. Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology 1991; 129:2471.
  179. Roden AC, Moser MT, Tri SD, et al. Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 2004; 173:6098.
  180. Goldberg GL, King CG, Nejat RA, et al. Luteinizing hormone-releasing hormone enhances T cell recovery following allogeneic bone marrow transplantation. J Immunol 2009; 182:5846.
  181. Erben RG, Eberle J, Stangassinger M. B lymphopoiesis is upregulated after orchiectomy and is correlated with estradiol but not testosterone serum levels in aged male rats. Horm Metab Res 2001; 33:491.
  182. Ellis TM, Moser MT, Le PT, et al. Alterations in peripheral B cells and B cell progenitors following androgen ablation in mice. Int Immunol 2001; 13:553.
  183. Erben RG, Raith S, Eberle J, Stangassinger M. Ovariectomy augments B lymphopoiesis and generation of monocyte-macrophage precursors in rat bone marrow. Am J Physiol 1998; 274:E476.
  184. Masuzawa T, Miyaura C, Onoe Y, et al. Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. J Clin Invest 1994; 94:1090.
  185. Dudakov JA, Goldberg GL, Reiseger JJ, et al. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J Immunol 2009; 182:6247.
  186. Goldberg GL, Sutherland JS, Hammet MV, et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 2005; 80:1604.
  187. Schmitt TM, Zúñiga-Pflücker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 2002; 17:749.
  188. Awong G, Herer E, Surh CD, et al. Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells. Blood 2009; 114:972.
  189. Reimann C, Dal Cortivo L, Hacein-Bey-Abina S, et al. Advances in adoptive immunotherapy to accelerate T-cellular immune reconstitution after HLA-incompatible hematopoietic stem cell transplantation. Immunotherapy 2010; 2:481.
  190. Zakrzewski JL, Suh D, Markley JC, et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat Biotechnol 2008; 26:453.
  191. Holland AM, Zakrzewski JL, Goldberg GL, et al. Adoptive precursor cell therapy to enhance immune reconstitution after hematopoietic stem cell transplantation in mouse and man. Semin Immunopathol 2008; 30:479.
  192. Vago L, Oliveira G, Bondanza A, et al. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation. Blood 2012; 120:1820.
  193. Gill J, Malin M, Holländer GA, Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 2002; 3:635.
  194. Bennett AR, Farley A, Blair NF, et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 2002; 16:803.
  195. Depreter MG, Blair NF, Gaskell TL, et al. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci U S A 2008; 105:961.
  196. Rossi SW, Chidgey AP, Parnell SM, et al. Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 2007; 37:2411.
  197. Jenkinson WE, Bacon A, White AJ, et al. An epithelial progenitor pool regulates thymus growth. J Immunol 2008; 181:6101.
  198. Bleul CC, Corbeaux T, Reuter A, et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 2006; 441:992.
  199. Bonfanti P, Claudinot S, Amici AW, et al. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 2010; 466:978.
  200. Chidgey AP, Seach N, Dudakov J, et al. Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches. Semin Immunopathol 2008; 30:457.
  201. Seach N, Layton D, Lim J, et al. Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies. Curr Opin Biotechnol 2007; 18:441.
  202. Ott HC, Matthiesen TS, Goh SK, et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med 2008; 14:213.
  203. Uygun BE, Soto-Gutierrez A, Yagi H, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 2010; 16:814.
  204. Ott HC, Clippinger B, Conrad C, et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 2010; 16:927.
  205. Petersen TH, Calle EA, Zhao L, et al. Tissue-engineered lungs for in vivo implantation. Science 2010; 329:538.
  206. Seach N, Mattesich M, Abberton K, et al. Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part C Methods 2010; 16:543.
Topic 16355 Version 16.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟