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Immune reconstitution after allogeneic stem cell transplantation with reduced-intensity conditioning regimens

Abstract

Reduced-intensity conditioning (RIC) regimens have been increasingly used as an alternative to conventional myeloablative conditioning (MAC) regimens for elderly patients, for patients medically infirm to qualify for conventional allogeneic stem cell transplantation (SCT), and for disorders in which traditional MAC-SCT are associated with high rates of non-relapse mortality. One of the theoretical advantages of RIC-SCT is that it might lend to better immune reconstitution after transplantation due to less damage of the thymus, allowing regeneration of naive T cells derived from prethymic donor stem cells, and due to the proliferation of immunologically competent host T cells that survive the conditioning regimen. Although limited, studies comparing immune recovery following RIC and MAC-SCT have been insightful. One of the main difficulties of these studies is the current spectrum of RIC protocols, which vary considerably in myeloablative and immunosuppressive potential, resulting in apparently contradictory findings. In spite of this, most reports have shown significant quantitative and/or qualitative differences in T- and B-cell reconstitution after RIC-SCT in comparison with conventional SCT. This paper will review current knowledge of immune reconstitution following RIC-SCT.

Introduction

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for a variety of malignant and non-malignant hematological disorders. However, treatment related mortality, ranging from 10 to >50%, has restricted the application of allo-SCT to otherwise healthy patients and younger than 55. In an attempt to extend allo-SCT to older patients and those with medical comorbidities, several investigators have developed reduced-intensity conditioning (RIC) regimens, lacking toxicities derived from high-dose chemo-radiotherapy. RIC protocols have been defined as regimens not intended to eradicate host hematopoiesis, but still intended to allow complete engraftment of donor stem cells, obtaining at the same time a graft-vs-malignancy effect.1 Most protocols are based on the combination of a purine analogous, usually fludarabine, with alkylating agents like busulfan, melphalan, idarubicine and cytarabine or cyclophosphamide.2, 3, 4, 5, 6 These protocols are associated with various degrees of myelosuppression ranging from minimal to severe. A second approach is based on the use of low dose of total body irradiation (TBI), either alone or in combination with fludarabine.7, 8 This strategy is followed by minimal hematopoietic and overall toxicities. Although most RIC regimens use cyclosporine A (CSA) and mycophenolate mofetil (MMF) as graft-vs-host disease (GvHD) prophylaxis, some of them also use antithymocyte globulin (ATG) or Campath-1H as in vivo T-cell depletion.9, 10, 11 The most common reduced intensity regimens are shown in Table 1.

Table 1 Most commonly used reduced-intensity regimens as reported to the Center for International Blood and Marrow Research (CIBMTR) by ascending myelosuppressive intensity

One of the theoretical advantages of RIC-SCT is that it might lend to better immune reconstitution after transplantation owing to less damage of the thymus, allowing regeneration of naive T cells derived from prethymic donor stem cells, and due to the proliferation of immunologically competent host T cells that survive the conditioning regimen. However, published studies have shown contradictory findings and, in only a few of them, results of RIC regimens have been compared with those obtained with fully myeloablative conditioning (MAC). Several factors contribute to the difficulty of the comparison between RIC-SCT and MAC-SCT in terms of immune reconstitution. So far, no randomized studies are available since RIC-SCT has generally been reserved for elderly patients, patients that have received a previous autologous SCT, or patients with organ dysfunction who are not candidates for MAC regimens. As mentioned before, the myelosuppressive and immunosuppressive capacities of diverse RIC regimens vary depending on the protocol and therefore, their impact on immune reconstitution after transplantation may be different. Some of them use ATG or Campath-1H, which may significantly influence immune reconstitution due to in vivo pre-transplant lymphoid depletion. Donor lymphocyte infusions frequently used after RIC-SCT could also contribute to the recovery of some immune functions. Moreover, source of stem cells (peripheral blood, bone marrow or umbilical cord blood), type of donor (sibling vs unrelated, matched vs mismatched) and age of the patients (pediatric vs adult patients) are important variables that have to be taken into account when immune recovery is analyzed.

T-cell reconstitution

Methods of analysis of T-cell reconstitution after SCT

Until recently, immunophenotypic analysis of peripheral blood by flow cytometry has been the main tool to quantify lymphocyte reconstitution after SCT. Thymopoiesis has been indirectly evaluated by measuring phenotypically naïve T cells in the circulation. Differential expression of CD45 isoforms has been used to identify the naïve vs the memory subpopulation of CD4+ and CD8+ cells.12 Thus, naïve CD4+ T cells can be identified by expression of CD45RA antigen, often in combination with CD62L. Besides CD45RA, identification of naïve CD8+ T cells requires other markers such as CD11a, CD27, CD28 and CD62L. Memory T cells can be detected by the expression of CD45RO on both CD4+ and CD8+ T-cell populations. Unfortunately, phenotypic markers are not reliable since naïve T cells can expand extrathymically without stimulation,13 and memory cells may spontaneously revert back to naïve phenotype.14

In 1998 Douek et al.15 reported the use of T-cell receptor excision circles (TRECs) as a new method to measure thymic function. TRECs are episomal excision products of the T-cell receptor (TCR) genes rearrangements that occur in maturing thymocytes. Intrathymic formation of a productive TCR α-gene requires deletion of the TCRδ-gene, which is positioned within the TCRα locus.16 The TCRδ-gene is flanked by two TCRδ deleting elements, δRec-ψJ-α, which preferentially rearrange to each other, thereby deleting the TCRδ locus.13 The deleted TCRδ-gene remains present as an extrachromosomal circular excision product.17 These TRECs do not replicate during mitosis and are thus diluted during cell division.18 With real-time quantitative polymerase chain reaction (PCR), TRECs can be detected and quantified, providing an excellent measure of thymic function during periods of reconstitution of the peripheral immune system.19

The diversity of the T-cell repertoire is partially determined by rearrangement and fusion between the V, D and J segments. This rearrangement combined with insertion and deletion of junctional nucleotides determines the size of the complementarity-determining region 3 (CDR3) of the TCR.20 The final result of this process is the generation of a large heterogeneous pool of the CDR3-size lengths that differ by three nucleotides within each TCR Vβ family. The CDR3 region is centrally involved in antigen recognition by forming the contact site between the TCR and the antigenic peptides bound by the major histocompatibility complex molecules. PCR-based TCR Vβ CDR3-size spectra typing analysis is a sensitive tool for examining the complexity and diversity of T-cell repertoire reconstitution after SCT.21

Thymic-independent T-cell reconstitution

T-cell reconstitution following RIC-SCT, similar to MAC-SCT, occurs via two predominant pathways: a thymic-dependent pathway that recapitulates ontogeny and a thymic-independent pathway termed ‘homeostatic peripheral expansion’ (HPE) that involves expansion of mature T cells, which survive the preparative regimen and/or are contained within the allograft. Nonetheless, multiple lines of evidence from murine models and human studies have demonstrated that, in the contrast to thymic production of T cells, peripheral expansion generates a T-cell pool with both quantitative and qualitative deficiencies, resulting in impaired functional immunity to stringent antigens.22 There are numbers of possible antigens that could drive these responses; these include minor histocompatibility antigens, tumor-derived antigens, and epitopes of infectious agents. One factor contributing to the limited effectiveness of HPE is the loss of T cells due to a high rate of apoptosis.23 Elevated rates of apoptosis during in vitro culture, related to an increased susceptibility to activation-induced cell death are a characteristic feature of this activated lymphocytes derived of peripheral expansion. Furthermore, the T-cell repertoire that is generated during HPE is restricted by the TCR specificities contained in the starting inocula and by antigens that drive this process.23

A summary of the characteristics of some reports analyzing the immune reconstitution after RIC-SCT is shown in Table 2. The general pattern of lymphocyte reconstitution after RIC is similar to that reported after MAC-SCT, characterized by a rapid recovery of NK cells and CD8+ T cells, and a slow recovery of CD4+ T lymphocytes with a predominance of memory CD4+ T cells. However, differences in the speed of lymphocyte recovery between RIC-SCT and MAC-SCT have been reported.

Table 2 Summary of the characteristics of some reports analyzing immune reconstitution after RIC-SCT

So far, three studies have shown a faster recovery of T lymphocytes in RIC-SCT recipients in comparison generally MAC-SCT patients. Schulenburg et al.24 prospectively examined immune recovery of 66 adult patients undergoing allogeneic SCT with either RIC (n=21) or MAC regimen (n=45). Conditioning regimens consisted of 2 Gy of TBI and fludarabine for RIC-SCT patients, and fractioned high-dose TBI and cyclophosphamide for those receiving MAC-SCT. In this study, no differences were observed between groups in the recovery of total leucocytes, NK-cells, or CD8+ T cells. However, CD4+ T-cell reconstitution was significantly faster after RIC-SCT than after conventional transplantation at 3 and 6 months after transplant. No differences were found at 1 year after SCT. In the report of Chao et al.,25 five adult patients undergoing mismatched unrelated cord blood transplantation were studied. The results were compared with previously published results of patients receiving a MAC-SCT with cord blood stem cells and identical GvHD prophylaxis, ATG dose and supportive care. Despite the small number of patients studied, more rapid recovery of T cells was observed after RIC-SCT, reaching normal levels of CD3+ T cells at 6–12 months after transplantation in comparison with 24 months in those patients receiving MAC-SCT. In agreement with these studies, the study by Jimenez et al.26 showed faster recovery of CD3+ and CD4+ T cells after RIC-SCT. In this study, a total of 51 consecutive patients undergoing SCT (RIC-SCT n=24 and MAC-SCT n=27) were evaluated. RIC and MAC regimens consisted of fludarabine in combination with low doses of busulfan, melphalan or TBI, and cyclophosphamide plus TBI (12 Gy), respectively. RIC and MAC-SCT groups were not truly matched for all characteristics; thus, a multivariate statistical model was used to analyze lymphocyte recovery adjusting for those factors likely to have a confounding effect on the comparison between groups such as age of the patients, type of donor, dose of infused stem cells and GvHD. These results showed that RIC regimen was the most important factor associated with a rapid recovery of CD3+ and CD4+ T cells at 1–6 months after transplantation. No differences were observed later after transplantation.

In contrast with these studies, other reports have not found significant differences between RIC and MAC-SCT in the counts of lymphocytes after transplant. The largest study analyzed immune recovery over the first year after RIC-SCT using 2 Gy of TBI with or without fludarabine, and compared the results with those of a MAC-SCT reference group, conditioned with high-dose chemotherapy alone or in combination with high-dose TBI.27 During the first 180 days after SCT, total and subsets counts of T cells, proliferative ability of T cells to viral stimulation, and antibody levels, were similar after either type of transplant. At 1 year, however, total and naïve CD4+ and CD8+ T cells were higher after MAC-SCT. The inclusion of patients treated with tandem autologous transplantation followed by RIC-SCT and the avoidance of TBI in some patients in MAC-SCT group might have influenced these results. It is interesting to point out that in this study RIC-SCT patients had significantly higher numbers of CMV-specific helper T cells and lower rates of CMV disease in the context of mixed chimerism. Reductions in the rate of other infectious complications were also observed during the first 3 months but not later after RIC-SCT. The authors concluded that the immunity of RIC-SCT recipients seems to be better than the immunity of MAC-SCT patients during the early period after transplantation.

Similar results were reported by other authors in smaller series of patients suggesting that survival of host lymphocytes to RIC regimen significantly contributes to immune recovery in these patients in the early period after transplantation.28, 29, 30, 31 Morecki et al.30 reported no differences in the number of T cells after RIC-SCT in comparison with MAC-SCT; however, RIC regimen hardly lowered the normal T cell-dependent mitogenic response in the first 3 months after transplant.

In other three studies, the results of spectratype analysis demonstrated that RIC-SCT results in an earlier reconstitution of T-cell repertoire complexity.25, 31, 32 Taken together, these qualitative differences might lead to faster development of effective immune response against infectious agents and residual host malignant cells.

The use of RIC regimens with ATG or Campath-1H as GvHD prophylaxis could have a deleterious effect on the thymic-independent pathway of lymphocyte reconstitution after transplantation. Several authors have reported significant delay of T lymphocyte recovery and high incidence of viral infections in these patients.33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 D'Sa et al.34 prospectively analyzed T-cell reconstitution in 19 patients with multiple myeloma undergoing RIC-SCT using low doses of fludarabine, melphalan, and in vivo T-cell depletion with 100 mg of Campath-1H. In these patients significant delay in T-cell recovery was observed, with CD3+ T-cell counts below normal for up to 21 months after transplant and both memory and naïve CD4+ T cells below normal throughout follow-up. In keeping with this, the patients had high incidence of viral infections, especially CMV reactivation, which occurred in 75% of seropositive patients. In the study by Dodero et al.35 the use of lower doses of Campath-1H (7.5–15 mg/m2) seemed to be associated with a more rapid recovery of T lymphocytes in comparison with the report above mentioned. However, this strategy did not reduce the risk of CMV reactivation.

Thymopoiesis after RIC-SCT

Thymic function after RIC-SCT has been less studied. It is well known that complete reconstitution of T-cell immunity requires the regeneration of new naïve T cells from the thymus. Because the thymus is progressively replaced by fat with age, thymus T-cell output has been assumed to be severely limited in healthy adults. This physiological involution of the thymus with age has been suggested to be an important cause of delayed T-cell reconstitution after SCT in adults. In fact, thymic recovery does not occur for several months following conventional MAC-SCT.

In the study by Jimenez et al.,26 thymopoiesis was evaluated by measuring phenotypically naïve T cells and TREC levels on sorted CD3+ T cells in the peripheral blood. TRECs are generated within the thymus and identify new thymic emigrants and those that have not divided. Similarly to MAC-SCT, CD4+ T-cell recovery in RIC-SCT patients consisted predominantly in memory CD4+ T cells; however, naïve CD4+ T cell counts were significantly higher at 3 and 6 months after RIC-SCT in comparison with MAC-SCT. Moreover, the proportion of patients with detectable TREC levels was significantly higher at 1 and 3 months after RIC-SCT. In comparison with TREC levels in healthy subjects, RIC-SCT patients reached normal TREC numbers at 6 months after transplantation, whereas patients in the MAC-SCT group did not. Available data indicate that there are no extrathymic anatomical sites with substantial TRECs bearing T-cell production.36 Therefore, the progressive increase of TREC levels in peripheral blood after RIC-SCT suggest slow but continuous production of thymic T cells that may reflect more rapid recovery of the thymic function in these patients. The majority of patients in the MAC-SCT group were conditioned with high-dose TBI, while only a few patients in the RIC-SCT group received TBI and it was at very low doses.

Since thymopoietic defects after transplantation may be due to the effects of radiation on the thymus microenvironment, it is reasonable to assume that the use of conditioning regimens avoiding high-dose TBI may reduce the toxicity over the thymus. Chung et al.37 reported that the dose of pre-transplant radiation has quantitative and qualitative effects on post-transplant thymopoiesis in mice. Increasing doses of radiation result in a lower regenerative capacity of the thymus and production of IL-7, a well-known stimulus for proliferation, survival and differentiation of immature thymocytes.

On the other hand, experimental and clinical experiences have demonstrated successful donor lymphohematopoietic engraftment following regimens using thymic irradiation.38, 39 In a murine model, stable mixed lymphohematopoietic chimerism was reliably achieved following low-dose TBI (300 cGy) or cyclophosphamide (200 mg/kg), peri-transplant monoclonal anti-T-cell antibody therapy directed against both host and donor T cells, thymic irradiation and major histocompatibility complex fully mismatched donor bone marrow transplantation. With the addition of post-transplant CSA, these animals were completely protected from acute and chronic GvHD even after delayed donor lymphocyte infusions (DLI).39 A similar nonmyeloablative regimen allowed induction of mixed lymphohematopoietic chimerism in patients with refractory hematologic malignancies.40, 41 Conditioning regimen consisted of cyclophosphamide (150–200 mg/kg), ATG (15–30 mg/kg/day on days −2, −1 and +1 or −1, +1,+3 and +5) and thymic irradiation. Post-transplant CSA was given as GvHD prophylaxis. This RIC regimen was associated with low incidence of acute GvHD and in one-half of the patients, a state of stable chimerism without GvHD was induced. The majority of these patients has achieved a complete remission and is progression-free.41

It has been suggested that the more rapid recovery of T cells after RIC-SCT could be the result of peripheral expansion of infused T cells instead of an actual preservation of thymic function. Bahceci et al.32 observed that naïve CD4+ T-cell numbers were significantly higher in RIC-SCT patients at all time points other than 1 year after transplant in comparison with T-cell depleted MAC-SCT. The levels of TRECs were also significantly higher in RIC recipients than in MAC patients at 45 days after transplant; however, they gradually decreased after the SCT. These data suggested that TRECs-positive cells were infused with the graft, and the ratio of TRECs-positive cells decreased with peripheral expansion of T cells. T-cell depletion of the graft and post-transplant donor lymphocyte infusions after MAC-SCT could, however, difficult the interpretation of these results. In this sense, we did not find any correlation between the numbers of naïve CD4+ T cells or TRECs on the stem cell harvest and the levels of them in the first months after transplantation (personal unpublished data, 2005).

Figure 1 schematically represents an interpretation of thymic-dependent and thymic-independent T-cell regeneration pathways after RIC and MAC-SCT according to the results above exposed.

Figure 1
figure1

Scheme for T-cell recovery after RIC and MAC-SCT. Reconstitution of the peripheral T-cell pool depends on thymic production of naïve TRECs positive cells (thymic-dependent pathway), and on peripheral expansion of preexisting or infused mature T cells (thymic-independent pathway). Contributions are made in varying proportions depending on several factors including the intensity of conditioning regimen. After RIC-SCT, thymic output seems to be higher than after MAC-SCT owing to a theoretical preservation of thymic function. Graft-vs-host disease, immunosuppressor drugs, and infections decrease naïve T cells and TRECs counts by a direct effect over the thymus and/or by an induction of division or apoptosis of peripheral blood naïve lymphocytes. Peripheral T-cell expansion after RIC-SCT could occur at a higher rate owing to the persistence of a higher amount of host residual mature T cells. The contribution to infused naïve T cells is still unknown.

B and NK cell reconstitution

Few studies address B-cell recovery and serum immunoglobulin levels after RIC-SCT transplantation. Maris et al.27 found similar total B-cell counts and IgD+ naïve B-cell counts in both RIC and MAC-SCT patients except at day 80 after SCT, when significant higher total and naïve B cells were noted among RIC patients. The levels of total IgG, total IgG2, and antibodies specific for S. pneumoniae and poliomyelitis virus in patients not given intravenous immunoglobulin after SCT were similar between the RIC and MAC-SCT recipients. In agreement with this study, three other reports showed no differences in the recovery of B-cell numbers between RIC and MAC-SCT.26, 29, 30 Although some authors have reported faster recovery of B cells after MAC-SCT, they did not find differences in serum immunoglobulin levels after transplantation except for faster recovery of IgM levels in RIC group.24, 28

NK cell recovery has not been studied in detail. Most studies have shown little or no significant differences when comparing the two modalities of conditioning regimens.24, 26, 29, 30

Dendritic cell reconstitution

Dendritic cells (DCs) constitute one of the key cellular components of innate and adaptive immunity to infections and antigens in vivo.42, 43 DCs are morphologically and phenotypically heterogeneous. They express high levels of major histocompatibility complex class II (HLA-DR++) and lack lineage-specific markers. In humans, two major distinct subsets of DCs have been identified, based on their expression of CD33 and CD123, namely myeloid (DC1) and plasmocytoid (DC2), respectively.44 Mature DC1 produce high levels of interleukin-12 and other TH1-polarising signals, whereas activated DC2 polarise T-cell differentiation into TH2 cells.45

Following allogeneic SCT, donor-derived DCs are detectable as early as 7–14 days after MAC-SCT and RIC-SCT, although they do not achieve normal values even at 1 year after transplantation.46, 47, 48 DC1 recovery thereby exceeds that of DC2, resulting in a significant increased DC1/DC2 ratio in comparison with normal donors.49, 50 No significant numeric differences are found between MAC-SCT and RIC-SCT.51

In a large prospective trial including both MAC-SCT and RIC-SCT patients a rapid and consistent establishment of DC1 and DC2 complete donor chimerism in over 70% of all patients was observed during the first 6 weeks after transplantation.52 The rate of patients with complete donor chimerism increased significantly over time within the first year after SCT. The authors did not find significant correlation between DCs or T-cell mixed chimerism and GvHD or relapse. In contrast to these results, Mohty et al.53 observed that high DC2 recovery profile at 3 months after RIC-SCT was associated with improved survival and a lower risk for late infection. Similarly, in another study, a low DCs count at the time of engraftment was associated with higher risk for death, relapse and acute GvHD after MAC-SCT and RIC-SCT.54

DCs chimerism may have an impact on graft-vs-host and graft-vs-leukemia effects. It has been reported that the persistence of host DCs at day +100 after transplantation correlates with the development of severe acute and chronic GvHD.55 Nachbaur et al.56 found that RIC-SCT patients with mixed monocyte-derived DCs (moDCs) chimerism have a significantly higher risk of relapse and lower risk of developing acute GvHD. Leukemic relapse and development of GvHD were preceded by loss of moDCs and conversion to full donor chimerism, respectively. These data suggest that, besides T-cell chimerism, DCs chimerism might be essential for full alloinmune response following RIC transplants.

Factors affecting immune reconstitution after RIC-SCT

Graft-vs-host disease

It is well known that GvHD is one of the main factors influencing both thymic-dependent and thymic-independent T-cell reconstitution after MAC-SCT. Several reports, using phenotypic lymphocyte analysis and/or TRECs quantification, have shown the association between GvHD and delayed T-cell reconstitution after transplantation.57, 58, 59, 60, 61, 62 GvHD can affect T-cell recovery in several different ways. First, a number of investigators have shown that GvHD induces thymic dysplasia associated with thymic involution, depletion of cortical and medullary thymocytes, epithelial cell destruction, and loss of Hassall's bodies, which collectively result in T-cell lymphopenia and a failure of negative selection of potentially autoreactive T cells.63, 64, 65, 66, 67 Moreover, because GvHD is treated with immunosuppressive drugs that may affect thymic function, the effect of GvHD on posttransplant T-lymphocyte recovery could be due to such drugs. Steroids and CSA are known to cause thymocytes and lymphocytes apoptosis in vitro and in mice experimental models. Second, TREC levels in peripheral blood T cells depend not only on thymic output, which increases TREC levels, but also on T-cell peripheral expansion, which decreases TREC levels. Increased numbers of cycling Ki67+ lymphocytes have been observed in patients with ongoing inflammatory processes such as GvHD. Combining TRECs quantification and Ki67+ analysis, Hazenberg et al.68 reported that increased peripheral T-cell division had a negative effect on TREC numbers.

Some investigators have reported a decreased incidence and severity of acute GvHD after RIC-SCT as compared with MAC-SCT with no differences in the incidence of chronic GvHD.69, 70 It could be suggested that the low incidence of acute GvHD instead of the type of conditioning regimen is responsible for more rapid immune recovery after RIC-SCT. In the study by Jimenez et al.26 comparing immune reconstitution after RIC-SCT vs MAC-SCT, GvHD was included in the multivariate analysis besides other variables such as type of conditioning regimen, type of donor, patient age, and dose of infused stem cells. The results showed that, whereas RIC regimen was the most important factor associated with a rapid recovery of naïve CD4+ T cells and TREC levels in the first months after transplantation, unrelated SCT and chronic GvHD were the only factors that significantly affect T-cell recovery and TREC numbers beyond 6 months after transplantation. No relationship between acute GvHD and T-cell recovery was observed. These results could suggest that chronic GvHD and/or its treatment at the late period after transplantation abrogate the early immunologic protective benefits of RIC-SCT. In agreement with these observations, Saito et al.71 did not observe any deleterious effect of acute GvHD on total, naïve and memory CD4+ T cells after RIC-SCT. These authors did not study the impact of chronic GvHD on immune reconstitution. On the contrary, Bahceci et al.32 did not find statistically significant differences in lymphocyte subsets nor in TREC levels when comparing RIC patients with or without GvHD. However, the low number of analyzed patients and the no distinction between acute and chronic GvHD prevent accurate conclusions from this study.

Patient's age

Several studies demonstrate that the human thymus is functional in healthy adults at least through approximately age 60.15, 72, 73, 74 However, it has been shown that TREC numbers decline exponentially in CD4+ and CD8+ T cells with age.15 Over the life of a person, the drop in the number of TRECs has been estimated in a 1–1.5 log10. Indeed, thymopoietic thymic epithelial space begins to atrophy at the age of one year, and shrinks in volume by 3%/year through middle age, then shrinks by <1%/year throughout the rest of life.74 This age-related thymic involution may affect the ability of the thymus to reconstitute T cells after SCT. A negative correlation between increasing age and numbers of naïve CD4+ T cells and TRECs after autologous and allogeneic SCT or chemotherapy has been reported in a variety of studies.75, 76, 77, 78, 79

Some studies in MAC-SCT setting have shown age as the main determinant of T-cell reconstitution after SCT. Eyrich et al.79 analyzed in a series of 164 pediatric recipients of allogeneic myeloablative transplantation (median age 7.5 years, range 0.3–22.6 years) the effect of recipient age, conditioning regimen, type of donor and graft, stem cell dose and GvHD on the onset and the plateau of thymic output after transplantation. Multivariate analysis showed that the onset on thymic output was inversely correlated only with recipient age, whereas the plateau of thymic output was higher in patients receiving increased stem cell numbers. Similarly, Storek et al.77 found that low TREC counts were associated with older patient age but not with CD34+ cell dose, stem cell source, conditioning (with or without irradiation), disease type, or acute or chronic GvHD. In contrast with these observations, Weinberg et al.57 reported that chronic GvHD was the most important factor that predicts low TREC levels. In this study, age did not affect TREC levels in patients with no GvHD through the age of 25 and had no effect on TREC levels of patients with active chronic GvHD at all ages. Moreover, in patients with resolved GvHD, there was an inverse correlation between age and TRECs above the age of 16 years. Similar results were been reported by other authors.34, 80

The effect of age on immune reconstitution after RIC-SCT has been less extensively analyzed. Savage et al.,81 in a group of nine patients receiving T-cell-depleted RIC-SCT observed that T-cell engraftment kinetics depended on patient's age. Adults became full donor chimeras faster than children but they had slower recovery of T- and B- cell number and function. In contrast with adults, pediatric patients achieved earlier normal numbers of naïve CD4+ T cells and showed a trend towards more TREC-positive cells, supporting the role of the thymus in naïve T cell reconstitution. B cells also recovered faster in children, which had normal B-cell counts by 1.5 months after SCT in comparison to adults that did not achieve normal B-cell counts until 1 year after transplantation.

In our experience, RIC regimen and not age was the most important predictor of early recovery of naïve T-cell numbers and TREC counts, whereas chronic GvHD was the main factor affecting thymic function 6 months after transplantation. It should be emphasized that this series of patients is constituted only by adult patients with a median of age of 57 years for RIC-SCT recipients and 34 years for MAC-SCT patients. Although it could be hypothesized that the low intensity of conditioning regimen could have overcome the effect of age on immune reconstitution, the differences in age between groups may not have been strong enough to identify the effect of this factor on thymic output.26

Chimerism

Peripheral expansion of host lymphocytes that survive conditioning regimen may contribute to immune reconstitution at least during the first months after RIC-SCT. The speed of lymphocyte donor engraftment depends on the intensity of the conditioning regimen. Low doses of TBI without fludarabine are associated with low donor chimerism levels, whereas the addition of fludarabine or the combination of fludarabine with cyclophosphamide or melphalan is associated with higher donor T-cell chimerism levels early after transplantation.82, 83, 84 Besides the intensity of conditioning regimen, donor chimerism levels after SCT depend on other factors such as type of hematologic disease, T-cell depletion of the graft, use of ATG, and type of post-grafting immunosuppression. Mixed chimerism was first described in patients with advanced acute leukemia or severe aplastic anemia, and further, in patients receiving T-cell depleted marrows after MAC-SCT.85, 86, 87 The use of ATG in RIC-SCT has been associated with a faster achievement of complete donor T cell chimera and with lower incidence of acute and chronic GvHD.88 Dose and concentration steady-state levels of MMF used as GvHD prophylaxis have been positively correlated with higher levels of donor T-cell chimerism.89, 90

Wu et al.91 used CDR3 spectra type analysis to examine the kinetics of T-cell-reconstitution following T-cell depleted MAC-SCT. They observed that complete donor chimerism strongly correlated with likelihood of restoration of T-cell repertoire complexity. In contrast, patients who demonstrated persistence of recipient hematopoiesis failed to reconstitute a diverse TCR repertoire. In the study by Bahceci et al.,32 RIC-SCT recipients achieved almost complete normalization of the T-cell repertoire by day 45 after transplantation. Seven out of 15 patients had 100% donor T-cell chimerism. Mixed chimerism did not have any deleterious or beneficial effect on absolute numbers of lymphocyte subsets, TREC levels or TCR spectra type complexity. Similarly, Friedman et al.31 reported more rapid T-cell repertoire reconstitution following RIC-SCT compared with myeloablative approaches. However, in this study, the effect of mixed chimerism was not analyzed since all patients achieved complete or full donor T-cell chimerism early after transplantation (median 32 days, range 17–50 days).

Several reports have shown a correlation between donor chimerism levels and incidence of GvHD, relapse, and rejection of the graft. In the study by Mattsson et al.92 T-cell chimerism was significantly correlated with decreased risk of moderate and severe acute GvHD and death by GvHD. However, the cumulative incidence of relapse did not show any statistical difference between patients with T-cell mixed chimerism and those with donor chimerism. On the contrary, Keil et al.93 in a study analyzing data from RIC-SCT patients using 2 Gy TBI and fludarabine found that patients with T cell chimerism on day 28 after transplantation were at higher risk of relapse and had a lower 2-year probability of progression-free survival than those with complete donor T cell chimerism. Other studies have confirmed the impact of achievement of full donor T- and NK- cell chimerism on RIC-SCT outcome using a variety of conditioning regimens such as 2 Gy TBI with or without fludarabine, fludarabine/busulfan or fludarabine/melphalan (Baron et al.94, Perez-Simon et al.95, Mohty M et al., Biol Blood Marrow Transplant 2006; 12 (Suppl 1): 33 (abstract)). Taken together these data suggest that patients at high risk of relapse might be identified early alter RIC-SCT by T-cell and NK-cell chimerism assessment. Prophylactic donor lymphocytes infusions could convert mixed to full donor T-cell chimerism and reduce the risk of relapse.96, 97

Concluding remarks

Immune reconstitution after RIC-SCT remains a field for debate. The current spectrum of RIC protocols, which vary considerably in myeloablative and immunosuppressive potential, and the absence of randomized studies comparing RIC-SCT to MAC-SCT, result in some difficulties to draw accurate conclusions. Published studies so far suggest that the use of RIC regimens in allogeneic SCT results in significant quantitative and/or qualitative differences in immune reconstitution in comparison with conventional MAC-SCT. Several authors have reported faster recovery of total lymphocytes, memory and naïve CD4+ lymphocytes, and TRECs levels at least during the first months after RIC-SCT. More rapid reconstitution of T-cell repertoire complexity has also been observed. A combination of thymus function preservation and peripheral expansion of donor and residual host mature lymphocytes could explain these results. Despite these differences, infectious complications and relapse remain major causes of morbidity and mortality after RIC-SCT. Several questions remain to be answered regarding the theoretical benefit of RIC-SCT in terms of immune reconstitution after transplantation. So far, it is unclear if different types of RIC regimens result in different kinetics of immune recovery. The optimal GvHD prophylaxis, immunosuppressive therapy after engraftment and prophylactic DLI strategy and their effect on immune reconstitution, incidence of infectious complications, and relapse remain to be determined.

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Acknowledgements

This work was supported in part by grants from Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Red Temática del Cáncer Instituto de Salud Carlos III n° CO3/10, FIS PI020622 and PI02/0350 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spanish Ministry of Health, and SGR2001 00375 from Generalitat de Catalunya.

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Correspondence to M Jiménez.

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Jiménez, M., Ercilla, G. & Martínez, C. Immune reconstitution after allogeneic stem cell transplantation with reduced-intensity conditioning regimens. Leukemia 21, 1628–1637 (2007). https://doi.org/10.1038/sj.leu.2404681

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Keywords

  • immune reconstitution
  • reduced-intensity conditioning regimen
  • allogeneic stem cell transplantation
  • TREC

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