Haploidentical Stem Cell Transplantation: High Doses of Alloreactive-T Cell Depleted Donor Lymphocytes Administered Post-Transplant Decrease Infections and Improve Survival without Causing Severe Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 512-512 ◽  
Author(s):  
Denis-Claude Roy ◽  
Silvy Lachance ◽  
Thomas Kiss ◽  
Sandra Cohen ◽  
Lambert Busque ◽  
...  

Abstract Abstract 512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
Author(s):  
A. John Barrett ◽  
Katayoun Rezvani ◽  
Scott Solomon ◽  
Anne M. Dickinson ◽  
Xiao N. Wang ◽  
...  

Abstract After allogeneic stem cell transplantation, the establishment of the donor’s immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell–antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1156-1156
Author(s):  
Jeff Davies ◽  
Marcos De Lima ◽  
Laurence Cooper ◽  
Thomas Spitzer ◽  
Neena Kapoor ◽  
...  

Abstract Haploidentical related donors extend availability of hematopoietic stem-cell transplantation (HSCT) to patients (pts) lacking HLA-matched family donors, but profound T-cell depletion (TCD) is needed to prevent severe GvHD, thus delaying immune reconstitution and increasing infection. Adoptive transfer of alloanergized donor T cells is an attractive approach to reconstituting T cell number and function with concomitant GVHD abrogation. We established proof-of-principle in haploidentical bone marrow (BM) transplant trials using ex vivo induction of recipient alloantigen-specific anergy in T cells within donor BM by allostimulation with blockade of CD28-mediated costimulation. This strategy permitted infusion of large doses of haploidentical T cells with donor BM, resulting in rapid immune reconstitution without excess severe GvHD or chronic GVHD. However the optimal dose of alloanergized donor T cells and their impact on functional antigen-specific immune reconstitution were not determined in our prior studies. We now report the results to date of a new study evaluating delayed infusion of escalating doses of donor PBMC anergized to recipient alloantigens after haploidentical HSCT. Alloanergized PBMCs were generated by co-culture of irradiated stimulator PBMC from a second haploidentical related donor (or the pt) using clinical grade humanized monoclonal anti-B7.1 and –B7.2 antibodies. 7 adults (median age 41, range 22–50) and 4 children (median age 7.5, range 2–14) with high risk leukemia/MDS (8 AML (3 CR1 4 CR2, 1 persistent disease), 2 high-IPSS MDS and 1 ALL (CR2) have been treated. Pts received fractionated TBI (1200cGy, n=5) or melphalan (140mg/m2, n=6), fludarabine, thiotepa and ATG followed by CliniMacs CD34-selected peripheral blood stem cells (PBSC) from haploidentical family donors without subsequent pharmacologic GVHD prophylaxis. Median infused cell doses (x 106/kg) were 9.4 (CD34+) and 0.02 (CD3+). All pts engrafted and attained full donor chimerism, with rapid neutrophil and platelet recovery (median D+11 and D+12, respectively). Using novel Bayesian phase I/II adaptive design, 10 pts have received donor PBMC after alloanergization (which resulted in a median 6-fold reduction in alloresponses): Dose (Ds)1, 103 CD3+ cells/kg (n=4), Ds2 104/kg (n=3) and Ds3 105/kg (n=3), infused on D+35 (n=8) or D+42 (n=2) without developing severe acute GvHD (Table). None of 5 evaluable pts developed chronic GvHD. At median follow-up of 8 months (range 1–23), 8/11 pts are alive. 6/11 pts are disease-free. 3 pts have died, from bacterial sepsis (Day +32), pulmonary veno-occlusive disease (D+59), and idiopathic pulmonary syndrome (D+78). Two AML pts have relapsed. Infusion of alloanergized donor PBMC appears to influence reconstitution of both CD4 T cell numbers and functional pathogen-specific T cells (Table). Normal SEB responses and functional CMV- and VZV-specific CD4 and CD8 T cells became detectable at 6–9 months in pts at Ds1, at 3 months in pts at Ds2 and at 2 months in the assessable pt at Ds3. Recovering T cells had a predominantly effector memory phenotype consistent with peripheral expansion of infused alloanergized donor T cells. These data suggest that delayed infusion of modest doses of alloanergized donor PBMC after haploidentical HSCT is not associated with significant GVHD, and may be associated with a dose-dependent improvement of quantitative and qualitative immune reconstitution. Ongoing recruitment of patients to higher alloanergized PBMC dose levels (up to 107/kg if tolerated) will determine the optimal dose that benefits immune reconstitution without causing severe GVHD. Infusion of Alloanergized PBMC GvHD New CMV reactivation Dose Level Pts T cell dose/kg Acute (Grade) Chronic Before PBMC infusion After PBMC infusion EBV/HSV infection after PBMC infusion Median time to CD4 ct &gt;100** (months) Months to detectable CMV/VZV IFN-gamma + T cells * only one evaluable pt at this time, TBD; to be determined: ** cells/microliter 1 4 103 0/4 0/2 2/4 0/4 2/4 9 6-9 2 3 104 1/3 (2) 0/3 2/3 0/3 0/3 4 3 3 3 105 1/3 (1) TBD 1/3 0/3 0/3 2* 2*


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 46-46
Author(s):  
Alessandra Forcina ◽  
Maddalena Noviello ◽  
Veronica Valtolina ◽  
Attilio Bondanza ◽  
Daniela Clerici ◽  
...  

Abstract Abstract 46 The broader application of haploidentical stem cell transplantation (haplo-HCT), is limited by the delayed immune reconstitution (IR) secondary to the procedures for GvHD prophylaxis. This ultimately results in a high-rate of infectious complications and non-relapse mortality. We dynamically analyzed immunoreconstitution (IR) in patients undergoing haplo-HCT for acute leukemias enrolled in two different phase I-II clinical trials aimed at improving IR. In the first trial (TK007), 28 patients (out of 50 enrolled) received suicide-gene transduced donor T cells at day +42 after a T-cell depleted graft, in the absence of post-transplant immunosuppression. In the second trial (TrRaMM), 40 patients received an unmanipulated graft and a rapamycin-based GvHD prophylaxis. T-cell immune reconstitution was more rapid in TrRaMM than in TK007 patients, with a threshold of CD3 cells>100/μl reached at days +30 and +90, respectively. In both trials IR was mainly composed of Th1/Tc1 lymphocytes with an inverted CD4/CD8 ratio. While in TrRaMM patients we observed an early expansion of naïve and central memory T cells, producing high amounts of IL-2, in TK patients IR was mainly composed of activated effectors. Furthermore, in TrRaMM patients we detected high levels of CD4+CD25+CD127- T regulatory cells (up to 15% of circulating T lymphocytes) that persisted after rapamycin withdrawal, and was significantly superior to that observed in TK patients and in healthy controls. Interestingly, in contrast to the different kinetics of T-cell reconstitution, no differences were observed in time required to gain protective levels of CMV-specific T cells, as shown by ψIFN ELISPOT analysis. Protective frequencies of CMV-specific lymphocytes were observed 3 months after HCT in both groups, a time-point that in TrRaMM patients corresponds to the average time of rapamycin withdrawal. In both trials the number of circulating CMV-specific T cells was inversely correlated to the number and severity of subsequent CMV reactivations and days of antiviral therapy. GvHD was diagnosed in 16 TrRaMM patients (40%) and in 10 TK patients (35% of patients who received TK cells). Severity of GvHD was different in the two cohort of patients with 5 TrRaMM patients (12,5%) and only 2 TK patients (7%) with grade III-IV GvHD. Of interest, in the TrRaMM group CMV-specific immunity was significantly hampered by the immunosuppressive treatment required to treat GvHD. On the contrary, in the TK group, the administration of ganciclovir was able to activate the suicide machinery and control GvHD without impairing viral-specific T-cell immunocompetence. These results matched with the kinetics of CMV reactivations. We observed that while in TrRaMM patients 80% of viral reactivations occurred after the immunosuppressive therapy, in TK patients no significant differences could be assessed before and after therapy. IFN-ψ ELISPOT might thus be a relevant and predictive test to guide patient-specific clinical monitoring and antiviral treatment. Overall, these results show that early immune reconstitution can be promoted in haplo-HCT by different strategies associated with a wide range of alloreactive potential. The risks and benefits associated with alloreactivity should guide the therapeutic choice tuned on patient disease status and co-morbidities. Disclosures: Bordignon: Molmed Spa: Employment.


Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1290-1298 ◽  
Author(s):  
Sarah Marktel ◽  
Zulma Magnani ◽  
Fabio Ciceri ◽  
Sabrina Cazzaniga ◽  
Stanley R. Riddell ◽  
...  

We have previously shown that the infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase(HSV-tk) gene is an efficient tool for controlling graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect. In addition to the GVL effect, the administration of donor HSV-tk+ cells could have a clinical impact in promoting immune reconstitution after T-cell–depleted stem cell transplantation (SCT). To explore this hypothesis, we have investigated whether in vitro polyclonal activation, retroviral transduction, immunoselection, and expansion affect the immune competence of donor T cells. We have observed that, after appropriate in vitro manipulation, T cells specific for antigens relevant in the context of SCT are preserved in terms of frequency, expression of T-cell receptor, proliferation, cytokine secretion, and lytic activity. A reduction in the frequency of allospecific T-cell precursors is observed after prolonged T-cell culture, suggesting that cell manipulation protocols involving a short culture time and high transduction efficiency are needed. Finally, the long-term persistence of HSV-tk+ cells was observed in a patient treated in the GVL clinical trial, and a reversion of the phenotype of HSV-tk+ cells from CD45RO+ to CD45RA+ was documented more than 2 years after the infusion. Based on all this evidence, we propose a clinical study of preemptive infusions of donor HSV-tk+ T cells after SCT from haploidentical donors to provide early immune reconstitution against infection and potential immune protection against disease recurrence.


2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiki Terao ◽  
Ken-ichi Matsuoka ◽  
Kentaro Narita ◽  
Takafumi Tsushima ◽  
Satoshi Yuyama ◽  
...  

The prevention of chronic graft-versus-host disease (cGVHD) is important for recipients of hematopoietic stem-cell transplantation (HSCT). As one of the etiologies, the relationship between early T-cell recovery and subsequent cGVHD development has been the focus of attention. Recently, letermovir (LTV) was approved for preventing cytomegalovirus (CMV) reactivation in the early transplantation phase. Although CMV affects the immune reconstitution after HSCT, the impacts of LTV to prevent CMV reactivation on early T-cell recovery and cGVHD have not been fully investigated. We aimed to identify early T-cell recovery under LTV at day 30 in 15 and 33 recipients from matched related donors (MRDs) and haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo), respectively. Early increases in the levels of total lymphocytes and HLA-DR+ activated T-cells at day 30 were observed under CMV prophylaxis by LTV only in PTCy-haplo recipients and not in MRD recipients. Moreover, PTCy-haplo recipients with LTV showed a significantly higher incidence of cGVHD, but not acute GVHD. Our observations suggest that an early increase in the levels of HLA-DR+ activated T-cells may be implicated in the development of cGVHD in patients treated with PTCy who received LTV. Further studies are warranted to validate our results and elucidate the detailed mechanisms of our new insights.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2909-2909 ◽  
Author(s):  
Paul J. Travers ◽  
Andrea Knight ◽  
Sarah Grace ◽  
Panos Kottaridis ◽  
Stephen Mackinnon ◽  
...  

Abstract In previous studies we and others have shown that the production of new T cells from the thymus declines after the third decade and that while patients below the age of 30 reconstitute primarily new T cells, those over thirty reconstitute primarily by expansion of pre-existing mature T cells. However little attention has been paid to the γδ subset of T cells, which form an important component of mucosal immune protection and which represent approximately 5% of peripheral T cells. Two major subsets of γδ T cells are defined by the expression of Vδ1 versus Vδ2, with Vδ1+ cells predominating in the fetal circulation and in mucosal sites, while Vδ2+ cells predominate in adult life and in the peripheral circulation. In light of the differerential preponderance of the two subsets in the fetal versus adult circulation, we have examined the reconstitution of these two subsets of γδ T cells following hemopoietic stem cell transplantation in a cohort of 28 patients sampled at 3 monthly intervals to ask whether both subsets recover adequately from adult stem cells. In 44 normal individuals, the median levels of Vδ1 and Vδ2 cells are 12.46 (0.22 to 167.8) and 32.78 (4.48 to 190.1) cells/mm3 respectively. In patients under 30, the reconstitution of the Vδ1 and Vδ2 subsets follow similar kinetics, reaching a plateau at 9 months post transplant with comparable numbers of Vδ1 and Vδ2 cells (note that the normal ratio of Vδ1 to Vδ2 is 0.38, so in the patients there is a significant increase in the proportion of Vδ1 cells in the peripheral circulation). In patients over 30 years of age, there is an even more significant disparity in the reconstitution of the two subsets. The Vδ1 subset recovers with similar kinetics as is seen in the patients under 30, although to slightly lower final levels. The Vδ2 subset, however, shows very little recover y, reaching a plateau at 6 months at the bottom of the normal range for up to 2 years post transplant. In these patients the ratio between Vδ1 and Vδ2 is inverted with an increasingly greater proportion of Vδ1 cells at longer times after transplant, with ratios in excess of 10 by 24 months post transplant, a 30-fold increase in the normal proportion of Vδ1 + T cells. Given that the Vδ1 subset shows a very restricted repertoire compared to the Vδ2 subset, the overall capacity of the circulating γδ T cell population to recognise and respond to antigen will be significantly compromised in older transplant recipients.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 578-578
Author(s):  
David Avigan ◽  
Jacalyn Rosenblatt ◽  
Baldev Vasir ◽  
Zekui Wu ◽  
Adam Bissonnette ◽  
...  

Abstract Autologous transplantation results in the transient reversal of tumor mediated tolerance due to the reduction in disease bulk, the depletion of regulatory T cells, and in the increased presence of tumor reactive lymphocytes during the period of lymphopoietic reconstitution. As a result, cancer vaccines are being explored as a means of targeting residual myeloma cells following stem cell transplant. We have developed a cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs). In this way multiple tumor antigens are presented in the context of DC mediated costimulation. We are conducting a study in which patients with multiple myeloma (MM) undergo stem cell transplantation followed by vaccination with 3 doses of DC/MM fusions. DCs were generated from adherent mononuclear cells cultured with GM-CSF and IL-4 for 5–7 days and matured with TNFa. DCs strongly expressed costimulatory and maturation markers. Myeloma cells were isolated from bone marrow aspirates and were identified by their expression of CD38, CD138, and/or MUC1. DC and MM cells were fused with polyethylene glycol as previously described and fusion cells were quantified by determining the percentage of cells that coexpress unique DC and myeloma antigens. To date, 19 patients have been enrolled and 18 have completed vaccine generation. Mean yield of the DC and myeloma preparations was 1.84 × 108 and 8.3 × 107 cells, respectively. Mean fusion efficiency was 40% and the mean cell dose was 4.3 × 106 fusion cells. As a measure of their potency as antigen presenting cells, fusion cells prominently stimulated allogeneic T cell proliferation in vitro. Mean stimulation indexes were 12, 57, and 31 for T cells stimulated by myeloma cells, DCs, and fusion cells, respectively. Adverse events judged to be potentially vaccine related included injection site reactions, pruritis, myalgias, fever, chills, and tachycardia. Six patients have completed the follow up period and 3 patients are currently undergoing vaccination. All patients achieved a partial response to transplant. Three patients demonstrated resolution of post-transplant paraprotein levels following vaccination. One patient with highly aggressive disease who experienced disease progression in the early post-transplant period, demonstrated initial response and then stabilization of disease with vaccination. We are examining the effect of transplant and vaccination on measures of cellular immunity, anti-tumor immunity and levels or activated as compared to regulatory T cells. T cell response to PHA mitogen was transiently depressed post-transplant. In contrast, a transient increase was noted post-transplant in mean T cell expression of IFNγ in response to autologous myeloma cell lysate. In preliminary studies, a relative increase in the ratio of activated (CD4/CD25low) to regulatory (CD4/CD25high) T cells was observed. To date, all evaluable patients demonstrated evidence of vaccine stimulated anti-tumor immunity as manifested by a rise in IFNγ expression by CD4 and/or CD8+ T cells following ex vivo exposure to autologous tumor lysate. In this ongoing study, fusion cell vaccination in conjunction with stem cell transplantation has been well tolerated, induced anti-tumor immunity and clinical responses in patients with multiple myeloma.


2020 ◽  
Vol 65 (1) ◽  
pp. 24-38
Author(s):  
N. N. Popova ◽  
V. G. Savchenko

Background. The timely reconstitution of the donor-derived immune system is a key factor in the prevention of such post-transplant complications as graft versus host disease, relapse or secondary tumours and various infections. These complications affect the long-term survival of patients after allogeneic stem cell transplantation.Aim — to describe the main stages of T Cell–mediated immune recovery in patients after allogeneic stem cell transplantation.General findings. T-cell–mediated immunity is responsible for anti-infective and anti-tumour immune response. The early post-transplant period is characterized by the thymus-independent pathway of T-cell recovery largely involving proliferation of mature donor T cells, which were transplanted to the patient together with hematopoietic stem cells. To a lesser extent, this recovery pathway is realized through the expansion of host naïve and memory T cells, which survived after conditioning. Thymus-dependent reconstitution involves generation of de novo naïve T cells and subsequent formation of a pool of memory T-cells providing the main immunological effects — graft versus tumour and graft versus host reactions. A better understanding of the T-cell immune reconstitution process is important for selecting optimized pre-transplant conditioning regimens and patient-specific immunosuppressive therapy approaches, thus reducing the risks of post-transplant complications and improving the long-term survival of patients after allogeneic stem cell transplantation.


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