Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

Immune reconstitution (IR) after allogeneic haematopoietic cell transplantation (HCT) represents a central determinant of the clinical post-transplant course, since the majority of transplant-related outcome parameters such as graft-vs.-host disease (GvHD), infectious complications, and relapse are related to the velocity, quantity and quality of immune cell recovery. Younger age at transplant has been identified as the most important positive prognostic factor for favourable IR post-transplant and, indeed, accelerated immune cell recovery in children is most likely the pivotal contributing factor to lower incidences of GvHD and infectious complications in paediatric allogeneic HCT. Although our knowledge about the mechanisms of IR has significantly increased over the recent years, strategies to influence IR are just evolving. In this review, we will discuss different patterns of IR during various time points post-transplant and their impact on outcome. Besides IR patterns and cellular phenotypes, recovery of antigen-specific immune cells, for example virus-specific T cells, has recently gained increasing interest, as certain threshold levels of antigen-specific T cells seem to confer protection against severe viral disease courses. In contrast, the association between IR and a possible graft-vs. leukaemia effect is less well-understood. Finally, we will present current concepts of how to improve IR and how this could change transplant procedures in the near future.

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Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation.

10.1101/2021.05.21.21257336 ◽

2021 ◽

Author(s):

Viktoriya Zelikson ◽

Amir Ahmed Toor ◽

Gary Simmons ◽

Natasha Raman ◽

Elizabeth Krieger ◽

...

Keyword(s):

T Cell ◽

Clinical Outcomes ◽

Cell Transplantation ◽

Immune Reconstitution ◽

Cellular Therapy ◽

Immune Cell ◽

Chronic Gvhd ◽

T Cell Response ◽

Cell Recovery ◽

Early Term

Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery, improved survival, and less chronic GVHD. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modeling 'early-term immune reconstitution' following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.

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New Developments in Allotransplant Immunology

Hematology ◽

10.1182/asheducation-2003.1.350 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 350-371 ◽

Cited By ~ 39

Author(s):

A. John Barrett ◽

Katayoun Rezvani ◽

Scott Solomon ◽

Anne M. Dickinson ◽

Xiao N. Wang ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Immune Reconstitution ◽

Cytokine Gene ◽

Post Transplant ◽

Cytokine Milieu ◽

Cytokine Gene Polymorphisms

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.

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Impaired immune reconstitution following allogeneic haematopoietic cell transplantation in children: Multivariate analysis of clinical risk factors

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2005.11.257 ◽

2006 ◽

Vol 12 (2) ◽

pp. 83

Author(s):

K. Kalwak ◽

E. Gorczynska ◽

D. Turkiewicz ◽

M. Ussowicz ◽

A. Dyla ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Cell Transplantation ◽

Immune Reconstitution ◽

Clinical Risk Factors ◽

Clinical Risk ◽

Haematopoietic Cell ◽

Allogeneic Haematopoietic Cell Transplantation

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Letermovir Administration to Prevent Cytomegalovirus Reactivation Is the Potential Risk of Chronic Graft-Versus-Host Disease in Patients Who Received Haploidentical Stem-Cell Transplantation With Post-Transplant Cyclophosphamide

Frontiers in Oncology ◽

10.3389/fonc.2021.666774 ◽

2021 ◽

Vol 11 ◽

Author(s):

Toshiki Terao ◽

Ken-ichi Matsuoka ◽

Kentaro Narita ◽

Takafumi Tsushima ◽

Satoshi Yuyama ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cell Recovery ◽

Activated T Cells ◽

Post Transplant ◽

Hla Dr ◽

Cmv Reactivation

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.

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Rapid Helper T-Cell Recovery at 3 Months Correlates to Successful Transplant Outcomes after Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5201.5201 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5201-5201

Author(s):

Joon Ho Moon ◽

Jin Ho Baek ◽

Dong Hwan Kim ◽

Sang Kyun Sohn ◽

Jong Gwang Kim ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

T Cell ◽

Immune Reconstitution ◽

Opportunistic Infections ◽

Helper T Cells ◽

Cell Recovery ◽

Helper T Cell ◽

Post Transplant ◽

Cell Counts

Abstract Background: The current study attempted to evaluate the role of a simple quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes, including overall survival (OS), non-relapse mortality (NRM), and opportunistic infections, after allogeneic stem cell transplantation (SCT). Methods: A total of 69 patients receiving an allogeneic SCT were included. The disease entities were as follows: AML 42, ALL 5, CML 15, NHL 5, and high-risk MDS 2. The peripheral lymphocyte subset counts, such as CD3+ T-cells, CD3+4+ helper T-cells, CD3+8+ cytotoxic T-cells, CD19+ B-cells, and CD56+ natural killer (NK) cells, were measured 3, 6, and 12 months post-transplant. Results: The CD19+ B-cell reconstitution was slow, while a rapid CD56+ NK cell recovery was noted. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (p<0.0001), NRM (p=0.0007), and opportunistic infections (p=0.0108) when stratifying patients with cut-off value of 200×106/L CD4+ helper T-cells. A rapid CD4+ helper T-cell recovery was also independently associated with a higher CD4+ helper T-cell transplant dose (p=0.006) and donor type (p<0.001) in a regression analysis. An early CD4+ helper T-cell recovery at 3 months was associated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate survival analysis, a combination of a higher CD34+ cell dose and rapid recovery of CD4+ helper T-cells at 3 months was found to a have favorable prognosis in terms of OS (p=0.001, hazard ratio [HR] 3.653) and NRM (p=0.005, HR 4.836), yet not relapse. Conclusion: A rapid recovery of the CD4+ helper T-cell count above 200×106/L at 3 months seemed to correlate with a faster immune reconstitution and predict a successful transplant outcome. Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months

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T-Cell Depleted Haematopoietic Stem Cells (HSC) Transplantation with Add Back of CD45RA Negative DLI: About 2 Cases

Blood ◽

10.1182/blood.v120.21.4350.4350 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4350-4350

Author(s):

Liliane Liliane Dal-Cortivo ◽

Rita Creidy ◽

Aurélie Gabrion ◽

Sébastien Héritier ◽

Guilhem Cros ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Immune Reconstitution ◽

Infectious Complications ◽

Post Transplant ◽

Cd8 T Lymphocytes ◽

Group 2 ◽

Hsc Transplantation ◽

Group 1

Abstract Abstract 4350 Introduction: Transplantation of T cell depleted (TCD) HSC transplantation has been associated with:1) an increased risk of infectious complications due to a very late immune reconstitution, 2) a non negligible risk of Graft Versus Host Disease (GVHD) requiring immunosuppressive therapy, and 3) an increased risk of graft rejection. It has been demonstrated that GVHD in murine models is mostly mediated by naïve T cells. Memory T cells have a reduced capacity to induce GVHD while preserving the anti-infectious capacity (Anderson BE et al., 2003). Removing CD45RA cells from donor lymphocytes could reduce infectious complications without induction of GVHD. This procedure was evaluated in two patients presenting multiple infections and treated with mismatch HSC transplantation. Methods: Post transplant immune reconstitution has been compared between two groups. Group 1: 7 patients (1 ostepetrosis, 1 Fanconi anemia and 5 Severe Combined Immuno Deficiency) transplanted with TCD HSC (age: 3 months-11 years, sex ratio F/M: 4/3). Group 2: 2 patients (1 ORAI1 deficiency and 1 MHC class II deficiency) transplanted with TCD HSC and CD45RA depleted cells of the CD34 negative fraction (age: 8 and 23 months, 1 female and 1 male). All patients had myeloablative conditioning regimen. CD34+ cell selection and CD45RA cell depletion procedures were performed using the Clini Macs system (Miltenyi Biotec). Group 1 received a median of 15.3 × 106CD34+ cells/kg with less than 5000 T lymphocytes/kg. Group 2 received respectively 8.8 and 12.3×106 CD34+ cells/kg with less than 5000 T lymphocytes/kg in HSC transplant and 0.9 and 9.2×106/kg CD45RO+ T cells. The thresholds of 100 CD4+ T lymphocytes and 50 CD8+ T lymphocytes per microliter at three months post transplantation, shown to allow sufficient protection against infectious complications (Hakki et al. 2003), were used in our analysis. Results: No significant difference in GVHD incidence was shown between the two groups since only 2/7 patients presented moderate GVHD in group 1 and no GHVD in group 2. Engrafment for both kind of pathology in group 2 was also remarkable Immune reconstitution of CD4+ and CD8+ T lymphocytes was earlier in group 2 as at one month we detected CD4+ T lymphocytes (430 and 24/μl) and CD8+ T lymphocytes (520 and 40/μl) respectively for patient 1 and 2. Whereas in group 1 no T lymphocytes were detected before two months post transplant. The number of CD4+ and CD8+ T lymphocytes at three months post transplantation was considerably increased in group 2 (CD4+: 609 and 190/μl; CD8+: 2088 and 95/μl) versus group 1 (CD4+: 14/μl; CD8+: 0.4/μl). Patient 1 in group 2 presented CMV reactivation at day 10 post transplant (87650 copies/ml, threshold 500) and was able to clear this infection at day 37 concomitantly to an increased CMV tetramer positive cells percentage (Tetramers at day 37/tetramers at day 10: 433 fold increase). Conclusion: The two patients treated with T-cell depleted haematopoietic stem cells (HSC) transplantation and add back of CD45RA negative DLI showed good engraftment, earlier and enhanced immune reconstitution without GVHD. Moreover, one patient developed specific and efficient anti-CMV response probably due to an expansion of the injected CD45RO T cells. These interesting preliminary results should be confirmed by a clinical trial. Disclosures: No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v114.22.512.512 ◽

2009 ◽

Vol 114 (22) ◽

pp. 512-512 ◽

Cited By ~ 6

Author(s):

Denis-Claude Roy ◽

Silvy Lachance ◽

Thomas Kiss ◽

Sandra Cohen ◽

Lambert Busque ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Immune Reconstitution ◽

Chronic Gvhd ◽

T Cell Depletion ◽

Post Transplant

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.

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