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Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation

Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation
Literature review current through: Sep 2023.
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 "Sources of hematopoietic stem 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 "Sources of hematopoietic stem cells", section on 'PBPC versus bone marrow for malignant disease'.)

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 "Sources of hematopoietic stem cells", section on 'Bone marrow' and "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Cell dose' and "Sources of hematopoietic stem cells", section on 'Optimal CD34 cell dose'.)

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.)

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Topic 16355 Version 16.0

References

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