POST TRANSPLANT IMMUNE RECONSTITUTION IN A PATIENT WITH AUTOINFLAMMATORYSYNDROME DUE TO SAMD9L MUTATION

2017 ◽  
Author(s):  
Analia Seminario
Keyword(s):  
Immune Reconstitution ◽  
Post Transplant

scholarly journals Chimerism, Immune Reconstitution and Outcome after Allogeneic Myeloablative and Reduced Intensity Unrelated and Haploidentical PBSC Transplantation Using Post-Transplant Cyclophosphamide

2015 ◽  
Vol 21 (2) ◽  
pp. S168-S169
Author(s):  
Ayman Saad ◽  
Racquel Innis-Shelton ◽  
Donna Salzman ◽  
Luciano J. Costa ◽  
Antonio di Stasi ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Post Transplant ◽  
Reduced Intensity

scholarly journals Early Immune Reconstitution after Haplo-Identical Hematopoietic Stem Cell Transplantation (HCT) with Post-Transplant Cyclophosphamide (PTCY) Does Not Improve Overall Survival Compared to Matched Unrelated Donor HCT Recipients Receiving Thymoglobulin Prophylaxis (ATG)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5676-5676
Author(s):  
Yasser Khaled ◽  
Joshua Boss ◽  
Poojitha Valasareddy ◽  
Arnel Pallera ◽  
Robert Johnson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Overall Survival ◽  
T Cell ◽  
Graft Failure ◽  
Immune Reconstitution ◽  
T Cell Proliferation ◽  
First Year ◽  
Post Transplant ◽  
Allogeneic Hct ◽  
Primary Graft Failure

Recent retrospective studies demonstrated similar overall survival (OS) and relapse rate after allogeneic HCT using matched unrelated or haplo-identical donors. However, differences in graft versus host disease (GVHD) prevention protocols using ATG or PTCY may have influenced the results. In addition, there is little knowledge about immune reconstitution after PTCY compared to ATG. We examined the outcomes of 73 consecutive patients who received allogeneic HCT from 5/2015 to 4/2019 (39 Haplo, 34 MUD). Patient's Characteristics shown in table-1. The two groups matched except for donor age, CD34 dose infused and race. Conditioning regimens shown in table-1. MUD recipients received GVHD prophylaxis with Tacrolimus/ Mycophenolate (Tacro/MMF) in addition to ATG (24 Patients) or PTCY (10 Patients) while Haploidentical patient received Tacro/MMF with PTCY. A panel of immune reconstitution markers collected at day 100 post- transplant for CD3, CD4, CD8, Activated T cell ( HLA- DR3+ CD3+)and NK cells ( CD56+) was obtained for 29 MUD and 28 Haploidentical recipients. We observed pronounced proliferation and recovery in all T cell subsets in Haploidentical patients compared to MUD patients at day 100 as shown in Fig-1. This robust T cell recovery in Haploidentical transplant patients with PTCY was statistically significant for CD3, CD4 and CD8. When Immune reconstitution for Haploidentical patients compared to MUD patients who received PTCY, it maintained its robust effect on T cell proliferation (Fig-2) although it did not reach statistical significance. The overall survival at one-year with median duration of follow up of 22.6 months was 61.5% and 82.3% for Haploidentical and MUD recipients respectively; P=0.14. There were 15 deaths during the first year in the Haploidentical patients (3 = relapse, 5 = severe cytokine release syndrome (CRS), 1=Veno-occlusive disease, 3= infection, 2=GVHD and 1 = primary graft failure). In contrast there were only six deaths in MUD patients (2= relapse, 3= GVHD and 1= infection). There was no deaths in MUD PTCY patients in the first year. There was no primary graft failure in either arm, however secondary graft failure occurred in 2 Haploidentical and 1 MUD patients. Median time to engraftment was 18 days for Haploidentical (range, 12-57) and 11.6 days for MUD (range, 10-18). Acute GVHD grade 2-4 developed in 35% in MUD and 23% in Haploidentical patients. Conclusions: We found robust early immune recovery after Haploidentical HCT compared to MUD HCT. The degree of HLA mismatch with Haploidentical HCT and antigen presentation may have contributed to pronounced T cell proliferation as the same effects was not observed in MUD HCT with PTCY. Despite the early recovery of T cells after Haploidentical HCT the overall survival did not exceed the overall survival with MUD HCT. Severe CRS contributed to the increased mortality seen in Haploidentical HCT patients. Further strategies are needed to decrease treatment related mortality with Haploidentical HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

New Developments in Allotransplant Immunology

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
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.

Donor DC Subsets Polarize Donor T-Cell Immune Responses in Allogeneic BMT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 573-573
Author(s):  
Jian-Ming Li ◽  
Cynthia Giver ◽  
Doug McMillan ◽  
Wayne Harris ◽  
David L. Jaye ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Peripheral Blood ◽  
Immune Reconstitution ◽  
Hematopoietic Cell ◽  
Post Transplant ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Introduction: Impaired or inappropriate immune reconstitution after allogeneic bone marrow transplantation (BMT) can lead to infection, graft-versus-host disease (GvHD) and leukemia relapse. We have previously reported that BM contains two populations of dendritic cell (DC) subsets, CD11b+ DC and CD11b− DC, and that CD11b depleted donor BM promoted increased donor T-cell chimerism and increased graft-versus-leukemia (GvL) activity in C57BL/6 → B10BR transplants [BBMT, 2004, 10: 540]. To explore the mechanism by which CD11b-depletion improved allo-reactivity, we performed allogeneic hematopoietic cell transplants using defined populations of donor stem cells, DCs, and T-cells in a MHC mis-matched BMT model. Methods: We transplanted FACS purified populations of 50,000 GFP+ CD11b- DC or CD11b+ DC in combination with 5,000 FACS purified Lin- Sca-1+ c-kit+ hematopoietic stem cells (HSC) and 300,000 or 1,000,000 congenic spleen T-cells from C57BL/6 donors into C57BL/6[H-2Kb], B10BR[H-2Kk] and PL/J[H-2Ku] recipients. Proliferation of CFSE stained donor T-cells was measured at 72 hours post-transplant. FACS cytometric bead array and intracellular cytokine staining measured serum and intracellular cytokines in donor T-cells. Results: The initial proliferation and Ki-67 expression of CFSE labeled donor T-cells in allogeneic recipients were much higher than in syngeneic recipients (homeostatic proliferation). Confocal microscopy showed co-localization of donor DC subsets with donor T-cells in the recipient spleens at 3 and 10 days post-transplant. In the allogeneic transplant settings, donor T-cells co-transplanted with CD11b- DC showed increased IFN-γ synthesis at 3 and 10 days post-transplant compared to donor T-cells co-transplanted with HSC plus CD11b+ DC or HSC alone. Increased proliferation of donor T-cells led to increased donor T-cell chimerism at day 10, 30, 60, and day105 post-transplant among recipients of CD11b- DC compared to recipients of HSC alone or HSC plus CD11b+ DC (Figure 1). Transplantation of spleen T-cells and CD11b- DC did not increase GvHD, but was associated with full donor chimerism. In contrast, transplantation of allogeneic CD11b+ DC led to persistence and expansion of residual host T-cells (Figure 2), increased numbers of donor CD4+CD25++Foxp3+ T-cells, and higher serum level of IL-10 supporting early post-transplant expansion of donor T regulatory cells (Treg). Conclusions: Donor CD11b- DC promoted immune reconstitution by polarizing donor T-cells to Th1 immune responses associated with increased IFN-γ synthesis and donor T-cell proliferation, while donor CD11b+ DC suppressed immune reconstitution by inhibiting donor T-cell allogeneic immune responses. These data support a novel paradigm for the regulation of post-transplant immunity and suggest clinical methods to test the hypothesis that manipulation of the DC content of a hematopoietic cell allograft regulates post transplant immunity in the clinical setting. Figure 1. Donor Spleen Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(+)DC and spleen T-cells] Figure 1. Donor Spleen Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(+)DC and spleen T-cells] Figure 2. Host Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(-)DC and spleen T-cells] Figure 2. Host Derived T-cells in Peripheral Blood [* p<0.05, v.s. recipients of HSC plus CD11b(-)DC and spleen T-cells]

Plasma Levels of Soluble Interleukin-7 Receptor Alpha (sIL-7Ra) and IL-7Ra Polymorphism After Allogeneic Stemcell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4012-4012 ◽  
Author(s):  
Zaiba Shamim ◽  
Stephanie Thiant ◽  
Sylvie Faucher ◽  
Bachra Choufi ◽  
Lars Ryder ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Conditioning Regimen ◽  
Elevated Serum ◽  
Biological Significance ◽  
Soluble Form ◽  
Healthy Individuals ◽  
Related Factors ◽  
Post Transplant ◽  
Interleukin 7 ◽  
Baseline Values

Abstract Abstract 4012 Background: Interleukin-7 (IL-7) is a cytokine essential for T cell development in the thymus and maintenance of peripheral T cells. IL-7 binds to cellular IL-7 receptors (IL-7Ra-common g chain heterodimer), in competition with a soluble form of the receptor, shed by the cells (sIL-7Ra). We have identified single nucleotide polymorphisms in the exons of the gene encoding IL-7Ra (+510T/C rs1494558, +1237 G/C rs1494555, 2087 C/T rs6897932), and previous results by us and by others indicate that IL-7R SNPs are associated with aGvHD and mortality after SCT. Moreover, the biological significance of +2087 C/T SNP has been suggested by the finding of elevated serum levels of sIL-7Ra in healthy individuals with 2087CC (Haplotype 4), also associated with increased alternative splicing of exon 6 and a higher frequency of recent thymic emigrants. We hypothesized that sIL-7Ra levels during SCT are influenced by genetic polymorphism and may play a role in immune reconstitution after SCT. Aims: 1) To investigate sIL-7Ra levels during SCT along with IL-7Ra genotypes and 2) to evaluate associations between sIL-7Ra levels and immune reconstitution and outcome in SCT. Patients and Methods: 122 patients undergoing SCT for haematological malignancies after either myeloablative (n= 52) or reduced intensity conditioning (n=70) were included. Donors were either matched siblings (n=68) or matched unrelated donors (n=54), and the patient age at the time of transplant was 50 years (6–67) (median (range)). sIL-7Ra levels were measured in plasma by a quantitative bead capture assay. IL-7Ra SNPs were determined by a SSP-PCR system and IL-7 was tested by ELISA (R&D) (n=77). Results: sIL-7Ra levels decreased during the course of transplantation from 113 ng/ml (32–558) at day −15 to 48 ng/ml (32–195) at day +14 (p=0.0001), and reached baseline levels again at day +60. sIL-7Ra levels were not associated with the intensity of the conditioning regimen. This pattern appeared to be inversely mirrored by the IL-7 levels, which increased from baseline values at day –14 of 2.4 pg/ml (0.3–17.6) to 11.3 pg/ml (2.0–30.2) (p<0.0001) at day +14, followed by a gradual decline down to baseline values at day +60. sIL-7Ra levels at day +90 were reduced in patients transplanted with donors carrying IL-7Ra 2087T allele, in line with our previous findings in healthy individuals (105 ng/ml (42–274) vs. 152 ng/ml (20–971), p=0.0015). In addition, post-transplant sIL-7Ra levels correlated with pre-transplant sIL-7Ra levels (r=0.39 p=0.0032), indicating that patient related factors in addition to the genotype of the donor lymphocytes may play a role in the regulation of sIL-7Ra levels post-transplant. sIL-7Ra appeared to be predictive of the rate of immune reconstitution by the finding that sIL-7Ra at day +14 correlated significantly with total lymphocyte counts post-transplant (day +90: r=0.28 (p=0.031) and day +180: r=0.55 (p<0.0001)). In contrast, IL-7Ra genotypes were not associated with immune lymphocyte counts post-transplant and early post-transplant IL-7 levels did not correlate significantly with lymphocyte counts at any stage. Outcomes: There was a trend towards an association between high sIL-7Ra levels and increased overall survival (p=0.057), but sIL-7Ra levels were unrelated to the occurrence of aGvHD. However, the IL-7/sIL-7Ra ratio at day +14 was significantly higher in patients with grade 2–4 aGvHD compared to grade 0–1 aGvHD (0.29 (0.04–0.73) vs 0.19 (0.01–0.8), p=0.033). Conclusion: The data of the present study indicates that sIL-7Ra levels after SCT are determined by the IL-7R 2087 genotype of the donor in addition to patient related factors. sIL-7Ra levels in the early phase post transplant is associated with the rate of lymphocyte recovery post-SCT. Thereby this study adds to the growing evidence suggesting the importance of the IL-7 axis in SCT. The study further suggests that monitoring sIL-7Ra levels post-transplant may help to guide the clinical use of IL-7. Disclosures: No relevant conflicts of interest to declare.

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