Cytokine-enhanced mixed lymphocyte reaction (MLR) in cord blood (original) (raw)
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Alloresponses of cord blood cells in primary mixed lymphocyte cultures
Human Immunology, 2002
The aim of this study was to compare the alloreactive responses against HLA antigens of cord blood cells with those of adult peripheral blood cells. In primary mixed lymphocyte cultures and bulk cell-mediated lympholysis experiments cord blood cells demonstrated significantly decreased proliferation and cytotoxicity. Experiments analyzing the specificity of anti-HLA cytotoxic T lymphocytes (CTL) revealed that cord blood (CB) CTL reacted only partially with third-party cells expressing the stimulating HLA antigens. Lower frequencies of IL-2 producing helper, cytotoxic T-cell precursors and IL-4 producing CB cells were found, whereas the frequencies of IFN-gamma producing cells, as determined by ELISpot experiments, were equivalent to the frequencies of adult IFN-gamma producing cells. Our results imply that, although CB cells have significantly decreased proliferative and cytotoxic alloresponses in bulk mixed lymphocyte cultures, their IFN-gamma production is comparable with that of adult mononuclear cells. Preserved production of IFN-gamma may be a risk factor for the development of graft-versus-host disease and should be taken into consideration when evaluating the possibility for stem cell transplantation with HLA-mismatched CB.
The Role of HLA in Cord Blood Transplantation
Bone Marrow Research, 2012
In recent years, umbilical cord blood (CB), a rich source of hematopoietic stem cells (HSC), has been used successfully as an alternative HSC source to treat a variety of hematologic, immunologic, genetic, and oncologic disorders. CB has several advantages, including prompt availability of the transplant, decrease of graft versus host disease (GVHD) and better long-term immune recovery, resulting in a similar long-term survival. Studies have shown that some degree of HLA mismatches is acceptable. This review is intended to outline the main aspects of HLA matching in different settings (related, pediatric, adult, or double-unit HSCT), its effect on transplantation outcome and the role of HLA in donor selection.
British Journal of Haematology, 2007
The dose of graft-nucleated cells and CD34 + haematopoietic progenitor cells are predictors of allogeneic engraftment and survival in umbilical cord blood (UCB) recipients. In this single institution prospective phase II trial, flow cytometric analyses of CD34 + progenitor and lymphocyte populations in unmodified single unit human leucocyte antigen (HLA)-disparate UCB grafts infused into 31 consecutive adults (median age 41 years, range 20-64) receiving myeloablative conditioning were compared with clinical outcomes. Median infused UCB graft-nucleated cells and CD34 + dose was 2AE2 · 10 7 /kg and 1AE2 · 10 5 /kg respectively. Day to absolute neutrophil count ‡0AE5 · 10 9 /l with full donor chimerism averaged 27 d (range 12-41). Univariate analyses demonstrated that UCB graft-infused cell doses of CD34 + (P = 0AE015), CD3 + (P = 0AE024) and CD34 + HLADR + CD38 + progenitors (P = 0AE043) correlated with neutrophil engraftment. This same analysis did not demonstrate a correlation between CD34 + (P = 0AE11), CD3 + (P = 0AE28) or CD34 + HLADR + CD38 + (P = 0AE108) cell dose and event-free survival (EFS). Highresolution matching for HLA-class II (DRB1) resulted in improved EFS (P = 0AE02) and decreased risk for acute graft-versus-host disease (GVHD) (P = 0AE004). Early mortality (prior to post-transplant day +28) occurred in three patients, while 26 patients achieved myeloid engraftment. These results suggest that UCB graft matching at DRB1 is an important risk factor for acute GVHD and survival, while higher UCB graft cell doses of CD34 + , committed CD34 + progenitors and CD3 + T cells favourably influence UCB allogeneic engraftment.
Antigen-Specific T-Lymphocyte Function After Cord Blood Transplantation
Biology of Blood and Marrow Transplantation, 2006
It has not been possible to determine the singular contribution of naive T lymphocytes to antigen-specific immunity after hematopoietic stem cell transplantation (HSCT), because of the confounding effects of donor-derived antigen-specific T lymphocytes present in most hematopoietic stem cell (HSC) products. Because umbilical cord blood contains only naive T lymphocytes, we longitudinally evaluated the recipients of unrelated cord blood transplantation (UCBT) for the presence of T lymphocytes with specificity for herpesviruses, to determine the contribution of the naive T lymphocytes to antigen-specific immune reconstitution after HSCT. Antigen-specific T lymphocytes were detected early after UCBT (herpes simplex virus on day 29; cytomegalovirus on day 44; varicella zoster virus on day 94). Overall, 66 of 153 UCBT recipients developed antigen-specific T lymphocytes to 1 or more herpesviruses during the evaluation period. The likelihood of developing antigen-specific T lymphocyte function was not associated with immunophenotypic T lymphocyte reconstitution, transplant cell dose, primary disease, or acute and chronic graft-versus-host disease. These results indicate that naive T lymphocytes present in the HSC inoculum can contribute to the generation of antigen-specific T-lymphocyte immunity early after transplantation.
Recipient-Specific Tolerance after HLA-Mismatched Umbilical Cord Blood Stem Cell Transplantation
Transplantation, 2005
Background. Lower incidence and severity of acute graft versus host disease (GVHD) has been observed in leukemia patients receiving HLA-mismatched umbilical cord (UCB) transplants. However, despite the increased use of UCB in stem cell transplantation, the mechanisms underlying these favorable outcomes are not well delineated. Methods. We analyzed antigen specific lymphocyte responses after transplant to determine whether the decreased allogeneic responsiveness of UCB lymphocytes is attributable to pan-unresponsiveness, lymphocyte repressive or recipient-specific tolerance. Results. Circulating lymphocytes collected early (3 months) after UCB transplant demonstrate a less naïve phenotype compared with that in the infused graft. Additionally, after transplant, circulating peripheral blood UCB-derived lymphocytes produced normal levels of interferon-␥ and proliferated normally when stimulated with mitogen or third party alloantigen. In contrast, when stimulated with recipient antigen, circulating lymphocytes emerging posttransplant did not proliferate nor produce interferon-␥. Moreover, analysis of interleukin-4 production revealed a Th2 response to recipient antigens. These data indicate early induction of immune tolerance of naïve UCB graft lymphocytes with skewing of transplant recipient-specific immune response towards Th2 cytokine profile. Conclusions. UCB graft lymphocyte immune naivety and observed early tolerance induction may contribute to the observed favorable GVHD incidence, despite infusion of HLA mismatch grafts in the unrelated allogeneic setting.
HLA-C and HLA-DQB1 compatibility in unrelated cord blood transplants
Haematologica, 1999
Umbilical cord blood (UCB) cells have been definitively proved to be a source of hematopoietic stem cells with repopulating capacity when transplanted into pediatric hosts with neoplastic or non-neoplastic disease. Moreover, due to the immaturity of the UCB lymphoid compartment, these transplants are usually associated with a low incidence and severity of GvHD. This clinical observation and the immaturity of the UCB lymphoid compartment justify the acceptance of UCB units which differ from their recipient by 1 or 2 HLA antigens of the six HLA A, B and DRB1 antigens conventionally typed. Whether the number and type of HLA disparities affect clinical outcome of UCB transplants has not, however, been clearly demonstrated yet. In the present study on 14 pediatric patients with high risk leukemia transplanted with UCB from unrelated donors, evaluation of HLA compatibility was extended to HLA-C and DQB1 genes and correlated to the engraftment rate and occurrence of GvHD. Conditioning regi...
T-lymphocyte recovery and function after cord blood transplantation
Immunologic Research, 2010
The Szabolcs Lab is focused on understanding the biology of donor-derived cellular immunity in recipients of allogeneic hematopoietic cell transplantation (HCT) that can be translated into new immunotherapy strategies. To this end, we are focused on developing novel laboratory approaches to analyze and augment immune recovery for high risk patient cohorts without increasing graft versus host disease (GVHD). Much of our work has focused on unrelated cord blood transplantation (UCBT) as the dominant clinical scenario and laboratory model. Our overarching goal is to minimize transplant related mortality and morbidity and render HLA-mismatched unrelated cord blood transplant a widely accepted safe cellular therapy. Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Our Lab has a major focus towards ex-vivo expansion of cord blood T cells with anti-apoptotic cytokines and CD3/CD28 co-stimulatory beads. Expanded lymphocytes lack alloreactivity against recipient and other allogeneic cells indicating a favorable safety profile from graft-versus-host disease. Nevertheless, expanded T cells can be primed subsequently against lymphoid and myeloid leukemia cells to generate tumor-specific cytotoxic T cells. These findings offer a major step in fulfilling critical biological requirements to quickly generate a cellular product ex vivo, using a negligible fraction of a cord blood graft that provides a flexible adoptive immunotherapy platform for both for children and adults.