Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 396-407 ◽  
Author(s):  
Sujith Samarasinghe ◽  
Christoph Mancao ◽  
Martin Pule ◽  
Niga Nawroly ◽  
Helen Karlsson ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Functional Characterization ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Third Party ◽  
Alloreactive T Cells

AbstractImmunotherapy with allodepleted donor T cells (ADTs) improves immunity after T cell–depleted stem cell transplantation, but infection/relapse remain problematic. To refine this approach, we characterized the expression of surface markers/cytokines on proliferating alloreactive T cells (ATs). CD25 was expressed on 83% of carboxyfluorescein diacetate succinimidyl esterdim ATs, confirming this as an excellent target for allodepletion. Seventy percent of CD25− ATs expressed CD71 (transferrin receptor), identifying this as a novel marker to target ATs persisting after CD25 depletion. Comparison of residual alloreactivity after combined CD25/71 versus CD25 immunomagnetic depletion showed enhanced depletion of alloreactivity to host with CD25/71 depletion in both secondary (2°) mixed lymphocyte reactions (P < .01) and interferon-γ enzyme-linked immunospot assays (P < .05) with no effect on third-party responses. In pentamer/interferon-γ enzyme-linked immunospot assays, antiviral responses to cytomegalovirus, Epstein-Barr virus, and adenovirus were preserved after CD25/71 allodepletion. CD25/71 ADTs can be redirected to recognize leukemic targets through lentiviral transfer of a chimeric anti-CD19ζ T-cell receptor. Finally, we have established conditions for clinically applicable CD25/71 allodepletion under European Union Good Manufacturing Practice conditions, resulting in highly effective, reproducible, and selective depletion of ATs (median residual alloreactivity to host in 2° mixed lymphocyte reaction of 0.39% vs third-party response of 62%, n = 5). This strategy enables further clinical studies of adoptive immunotherapy with larger doses of ADTs to enhance immune reconstitution after T cell-depleted stem cell transplantation.

Clonality Analysis as a Tool To Study the Immunologic Reconstitution with Leukemia Patients Following Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5020-5020
Author(s):  
Xin Du ◽  
Yangqiu Li ◽  
Jianyu Weng ◽  
Zesheng Lu ◽  
Rong Xie ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Gene Repertoire ◽  
Hematopoietic Stem ◽  
Receptor Repertoire

Abstract Introduction The extensive diversity of the mature T-cell receptor(TCR) is determined primarily by the complementarity-determining regions (CDR3) of the TCR. The CDR3 of both TCRα and TCRβ genes is generated by extensive rearrangement and fusion between the V,D,and J segments and by random insertion and deletion of junctional nucleotides, which yields final products that are quite heterogeneous in size. As a result of these gene rearrangements, each T cell has a unique TCR and the diversity of the T-cell repertoire at any specific time can be characterized by the examination of CDR3 within that population. Using CDR3 spectratying technique, normal individuals demonstrate a highly diverse and polyclonal The aim of our study was to evaluate to investigate restricted expansion of TCR Vβ gene repertoire and the reconstitution of T cell receptor repertoire following allogeneic hematopoietic stem cell transplantation. Methods Patients Ten patients(9 males, 1 females; median age 31 years,range18–45) with 6 chronic myeloid leukemia-chronic phase and 4 cases of acute myelogenous lenkemia(CR1) who underwent HLA-matching sibling or unrelated BMT and/or peripheral blood stem cell transplantation (PBSCT) at our department between July 1999 and May 2000 were considered evaluable restricted expansion of TCR Vβ gene repertoire, the reconstitution of T cell receptor repertoire and oligoclonal T Cell Expansion in Chronic Graft-Versus-Host Disease. RT-PCR and Genes scan analysis (CDR 3 length analysis). Results Only 2-18Vβ genes were found in samples from these ten patients within one year, and there are different distribution in different patients. TCR repertoire complexity was abnormal in all patients, parts of the genes were expansion and part of them were suppressed. Samples from 9 patients with GVHD show V β3 in 7 cases, V β 8 and V β 23 in 6 patients. The results of genescan show that the PCR production of peripheral blood samples from these patients disply oligoclonal. Only 5–22Vβ subfamily T cells were found in samples from these patients whose transplantation more than one year. TCR repertoire complexity was abnormal in all patients. Discussion Following allogeneic BMT, regeneration of T-cell populations with a diverse repertoire can occure by at least two mechanisms: One mechanism is a thymic-dependent pathway, which presumably involves both negative and positive selection and recapitulates fetal ontogeny. Alternatively, regeneration of peripheral T cells may occur through thymic-independent mechanisms. All patients had marked abnormalities in their spectratypes, only 5-22Vβ subfamily T cells were found in samples from these patients, most of it was influenced after transplant, although the number of circulating CD3+ T lymphocytes in these patients have restored at normal lever by flow cytometic analysis, but the CD4+ T cell subset returned slowly in these patients resulting in an inversion of the normal CD4/CD8 ratio for more than 1 year after tuansplantation. Therefore, the analysis of TCRVβ subfamily is a usuaful methods and techniques for monitoring immune reconstitution after transplant.

scholarly journals Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients

2005 ◽  
Vol 201 (5) ◽  
pp. 805-816 ◽  
Author(s):  
Paolo A. Muraro ◽  
Daniel C. Douek ◽  
Amy Packer ◽  
Katherine Chung ◽  
Francisco J. Guenaga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multiple Sclerosis Patients

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4+ T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.

A Phase I/II Study of Xcellerated T Cells™ after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 925-925
Author(s):  
David Siegel ◽  
Ravi Vij ◽  
Robert A. Vescio ◽  
Ivan M. Borrello ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Post Transplant

Abstract Background: Previous studies have demonstrated a correlation between survival and lymphocyte recovery following autologous transplantation in subjects with multiple myeloma and other malignancies (Porrata et al., Blood 2001). We initiated a trial in the transplant setting to evaluate the activity of T cells activated and expanded ex vivo with the Xcellerate™ Process, which uses anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™ -Dynabeads®). Methods: Following induction therapy, patients underwent leukapheresis to collect peripheral blood mononuclear cells for the Xcellerate Process. Patients then underwent stem cell mobilization and collection, followed by high dose melphalan (200 mg/m2). Three days following peripheral blood stem cell infusion, subjects received 50–100 x 109 Xcellerated T Cells. Results: 36 subjects were treated. The median last f/u visit is 180 days post-transplant (range 90–450). A WaveBioreactor-based Xcellerate III Process, which was instituted in the last 18 subjects, resulted in 249 ± 90 fold (mean ± SD) T cell expansion. There were 93.6 ± 0.8 x 109 cells infused, which were 97.6 + 4.0% T cells. There were no Grade 3 or 4 acute infusional toxicities. Days of neutropenia and thrombocytopenia were 5 (3–43) and 4.5 (0–128) respectively [median (range)]. There were a median of 2 (range 0–14) units of packed red blood cell transfusions in 18/31 (58%) of subjects and a median of 0 (range 0–22) platelet transfusions in 15/31 (48%) of subjects. There were serious or Grade 3 infections in 5/29 (17%) of subjects, and mucositis in 5/29 (17%) of subjects (all ≤ Grade 2). Median days of hospitalization were 16 (range 10–70). Lymphocyte recovery was rapid, with counts reaching > 500/mm3 generally within 1–2 days following T cell infusion. Historically, lymphocyte recovery to > 500/mm3 usually does not occur for 3 or more weeks post-transplant. The rapid lymphocyte recovery included both CD4+ and CD8+ T cells. The mean (± SEM) CD4+ T cell count at 90 days post-transplant was 1,210 ± 80/mm3, significantly higher than that for historical controls receiving the same treatment regimen without Xcellerated T Cells (198 ± 72). The T cell receptor repertoire measured 25 days after the Xcellerated T Cell infusion demonstrated a normal pattern (n = 4/5). This is in contrast to the severe skewing of T cell receptor diversity observed in myeloma subjects following standard autologous stem cell transplantation (Mariani et al, BJH 2001). In 35 evaluable patients, preliminary results demonstrated 6% CRs, 46% VGPRs, 34% PRs, and 11% with PD, using the M-protein at diagnosis as reference. There have been no reported deaths to date. Conclusions: In multiple myeloma subjects, administration of Xcellerated T Cells following high-dose chemotherapy and autologous stem cell transplantation leads to rapid lymphocyte recovery and appears to restore a normal T cell receptor repertoire. The majority of subjects achieve clinical responses in the autologous transplant setting.

scholarly journals Alpha/Beta T-Cell Depleted Grafts as an Immunological Booster to Treat Graft Failure after Hematopoietic Stem Cell Transplantation with HLA-Matched Related and Unrelated Donors

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
E. Rådestad ◽  
H. Wikell ◽  
M. Engström ◽  
E. Watz ◽  
B. Sundberg ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Unrelated Donors

Allogeneic hematopoietic stem cell transplantation is associated with several complications and risk factors, for example, graft versus host disease (GVHD), viral infections, relapse, and graft rejection. While high levels of CD3+ cells in grafts can contribute to GVHD, they also promote the graft versus leukemia (GVL) effect. Infusions of extra lymphocytes from the original stem cell donor can be used as a treatment after transplantation for relapse or poor immune reconstitution but also they increase the risk for GVHD. In peripheral blood, 95% of T-cells express theαβT-cell receptor and the remaining T-cells express theγδT-cell receptor. AsαβT-cells are the primary mediators of GVHD, depleting them from the graft should reduce this risk. In this pilot study, five patients transplanted with HLA-matched related and unrelated donors were treated withαβT-cell depleted stem cell boosts. The majority ofγδT-cells in the grafts expressedVδ2and/orVγ9. Most patients receivingαβ-depleted stem cell boosts increased their levels of white blood cells, platelets, and/or granulocytes 30 days after infusion. No signs of GVHD or other side effects were detected. A larger pool of patients with longer follow-up time is needed to confirm the data in this study.

scholarly journals Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted

2021 ◽  
Vol 5 (17) ◽  
pp. 3309-3321
Author(s):  
Jeremy D. Rubinstein ◽  
Xiang Zhu ◽  
Thomas Leemhuis ◽  
Giang Pham ◽  
Lorraine Ray ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
T Cell Response ◽  
Third Party ◽  
Viral Control ◽  
Hematopoietic Stem

Abstract Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo–generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.

Adoptive Immunotherapy after Haploidentical Stem Cell Transplantation with T Cells Allodepleted by Photodynamic Purging

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1157-1157
Author(s):  
Katia Perruccio ◽  
Fabiana Topini ◽  
Antonella Tosti ◽  
Alessandra Carotti ◽  
Teresa Aloisi ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Adoptive Immunotherapy ◽  
Cell Responses ◽  
Alloreactive T Cells ◽  
Haploidentical Stem Cell Transplantation ◽  
Donor T Cells

Abstract After haploidentical stem cell transplantation, immune recovery is slow due to decaying thymic function and extensive T-cell depletion of the graft which is needed to prevent Graft-versus-Host Disease (GvHD). Consequently, infectious related mortality is about 30–40%. To address this problem, we investigated the efficacy of adoptive immunotherapy after photodynamic purging of alloreactive T cells (ATIR, Kiadis Pharma, Amsterdam, The Netherlands) in preventing GvHD and improving immune reconstitution. The 4,5-dibromorhodamine methyl ester (TH9402) is a photosensitizer structurally similar to rhodamine. When donor T cells are activated with allogeneic cells, they retain TH9402 which becomes highly cytotoxic upon activation with visible light. MLR-activated donor T cells are exposed to a fluorescent-light scanning device to eliminate alloreactive T cells. We designed a protocol which provided 3,260 ± 450 (mean ± SD)-fold allodepletion, full retention of T-regulatory cells, and preservation of pathogen- and leukaemia-specific T-cell responses (against Aspergillus, Candida, Cytomegalovirus (CMV), Adenovirus (ADV), Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), Toxoplasma antigens; and against leukaemia cells and leukaemia antigens (WT1 and Ca125)). Optimized protocol conditions are: MLR cell concentration: 3–5 × 10e6/ml; MLR duration: 24 hours; TH9402 concentration: 5 μM; TH9402 incorporation, as measured by median fluorescence index (MFI): 20,000 – 25,000; energy delivery: 0.1 J/cm2. Here we present the preliminary results of a clinical trial. Escalating doses of photodynamically allodeleted donor T cells, i.e., 1.25 × 10e5/Kg, 2.5 × 10e5/Kg, 5 × 10e5/Kg, 1 × 10e6/Kg and 1.25 × 10e6/Kg, were infused into groups of haploidentical transplant recipients. Only 1 patient developed grade III aGvHD at the 1 × 10e6/Kg cell dose and responded to immune suppressive treatment. Immune assessment analyses revealed that infusion of cell doses equal or greater than 5 × 10e5/Kg are associated with significant reconstitution of T-cell counts and appearance of pathogen-specific T-cell responses. One month after infusion, CD4+ and CD8+ T cells were 124 ± 54/cmm and 327 ± 42/cmm (versus 11 ± 4/cmm and 8 ± 4/cmm respectively, in patients receiving T-cell doses below 5 × 10e5/Kg, P = 0.0007). Aspergillus, Candida, CMV, ADV, HSV, VZV, Toxoplasma-specific CD4+ and CD8+ T-cell responses had recovered to frequencies within the normal ranges while they were absent in patients who received T cell doses under 5 × 10e5/Kg (P = 0.0002). In conclusion, this study demonstrates the feasibility, safety and preliminary indications of efficacy of adoptive immunotherapy after photodynamic purging of alloreactive T cells in recipients of haploidentical stem cell transplantation. A larger study will evaluate the impact of these T-cell infusions on transplant related mortality and disease free survival.

T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3449-3453 ◽  
Author(s):  
Mette D. Hazenberg ◽  
Sigrid A. Otto ◽  
Elmar S. de Pauw ◽  
Helene Roelofs ◽  
Willem E. Fibbe ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Cell Division ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Clinical Events

Abstract It is generally believed that homeostatic responses regulate T-cell recovery after peripheral stem cell transplantation (PSCT). We studied in detail immune recovery in relation to T-cell depletion and clinical events in a group of adult patients who underwent PSCT because of hematologic malignancies. Initially, significantly increased proportions of dividing naive, memory, and effector CD4+and CD8+ T cells were found that readily declined, despite still very low numbers of CD4+ and CD8+ T cells. After PSCT, increased T-cell division rates reflected immune activation because they were associated with episodes of infectious disease and graft-versus-host disease (GVHD). T-cell receptor excision circles (TRECs) were measured to monitor thymic output of naive T cells. Mean TREC content normalized rapidly after PSCT, long before naive T-cell numbers had significantly recovered. This is compatible with the continuous thymic production of TREC+ naive T cells and does not reflect homeostatic increases of thymic output. TREC content was decreased in patients with GVHD and infectious complications, which may be explained by the dilution of TRECs resulting from increased proliferation. Combining TREC and Ki67 analysis with repopulation kinetics led to the novel insight that recovery of TREC content and increased T-cell division during immune reconstitution after transplantation are related to clinical events rather than to homeostatic adaptation to T-cell depletion.

scholarly journals Early Reconstitution of Antibody Secreting Cells after Allogeneic Stem Cell Transplantation

2022 ◽  
Vol 11 (1) ◽  
pp. 270
Author(s):  
Martina Hinterleitner ◽  
Clemens Hinterleitner ◽  
Elke Malenke ◽  
Birgit Federmann ◽  
Ursula Holzer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Antibody Secreting Cells

Immune cell reconstitution after stem cell transplantation is allocated over several stages. Whereas cells mediating innate immunity recover rapidly, adaptive immune cells, including T and B cells, recover slowly over several months. In this study we investigated kinetics and reconstitution of de novo B cell formation in patients receiving CD3 and CD19 depleted haploidentical stem cell transplantation with additional in vivo T cell depletion with monoclonal anti-CD3 antibody. This model enables a detailed in vivo evaluation of hierarchy and attribution of defined lymphocyte populations without skewing by mTOR- or NFAT-inhibitors. As expected CD3+ T cells and their subsets had delayed reconstitution (<100 cells/μL at day +90). Well defined CD19+ B lymphocytes of naïve and memory phenotype were detected at day +60. Remarkably, we observed a very early reconstitution of antibody-secreting cells (ASC) at day +14. These ASC carried the HLA-haplotype of the donor and secreted the isotypes IgM and IgA more prevalent than IgG. They correlated with a population of CD19− CD27− CD38low/+ CD138− cells. Of note, reconstitution of this ASC occurred without detectable circulating T cells and before increase of BAFF or other B cell stimulating factors. In summary, we describe a rapid reconstitution of peripheral blood ASC after CD3 and CD19 depleted haploidentical stem cell transplantation, far preceding detection of naïve and memory type B cells. Incidence before T cell reconstitution and spontaneous secretion of immunoglobulins allocate these early ASC to innate immunity, eventually maintaining natural antibody levels.

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.

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