Donor-specific Immune Regulation by CD8 + Lymphocytes Expanded from Rejecting Human Cardiac Allografts

Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
American Journal of Transplantation (Impact Factor: 5.68). 02/2009; 9(2):397-403. DOI: 10.1111/j.1600-6143.2008.02498.x
Source: PubMed


To assess whether regulatory T cells are present in rejecting human cardiac allografts, we performed functional analyses of graft lymphocytes (GLs) expanded from endomyocardial biopsies (EMB; n = 5) with histological signs of acute cellular rejection. The GL cultures were tested for their proliferative capacity and regulatory activity on allogeneic-stimulated peripheral blood mononuclear cells (PBMC) of the patient (ratio PBMC:GLs = 5:1). Three of these GL cultures were hyporesponsive to donor antigens and suppressed the antidonor proliferative T-cell response of PBMC, but not the anti-third-party response. Interestingly, it was the CD8(+) GL subset of these cultures that inhibited the antidonor response (65-91% inhibition of the proportion of proliferating cells); the CD4(+) GLs of the expanded GL cultures were not suppressive. In conclusion, CD8(+) GLs expanded from rejecting human cardiac allografts can exhibit donor-specific immune regulatory activities in vitro. We suggest that during acute cellular rejection, GLs may not only consist of graft-destructing effector T cells, but also of cells of the CD8(+) type with the potential to specifically inhibit antidonor immune reactivity.

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    • "Great interest has been focused on CD4+ Tregs [1], and cell therapies using adoptive transfer of in vitro generated CD4+ Treg cells have demonstrated promising efficacy for immunomodulation in animal models of allogeneic transplantation as well as in clinical trials of human allogeneic bone marrow transplantation for the control of graft versus host disease [2], [3], [4]. However, evidence also suggests that CD8+ Tregs may play an important regulatory role in transplant tolerance [5], [6], [7], [8], in addition to possible immunomodulatory roles in autoimmune disorders [9], [10], cancers [11] and aging [12]. Several subsets of CD8+ Tregs have been observed. "
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    ABSTRACT: Human CD8(+) regulatory T cells, particularly the CD8(+)CD28(-) T suppressor cells, have emerged as an important modulator of alloimmunity. Understanding the conditions under which these cells are induced and/or expanded would greatly facilitate their application in future clinical trials. In the current study, we develop a novel strategy that combines common gamma chain (γc) cytokines IL-2, IL-7 and IL-15 and donor antigen presenting cells (APCs) to stimulate full HLA-mismatched allogeneic human CD8(+) T cells which results in significant expansions of donor-specific CD8(+)CD28(-) T suppressor cells in vitro. The expanded CD8(+)CD28(-) T cells exhibit increased expressions of CTLA-4, FoxP3, and CD25, while down-regulate expressions of CD56, CD57, CD127, and perforin. Furthermore, these cells suppress proliferation of CD4(+) T cells in a contact-dependent and cytokine-independent manner. Interestingly, the specificity of suppression is restricted by the donor HLA class I antigens but promiscuous to HLA class II antigens, providing a potential mechanism for linked suppression. Taken together, our results demonstrate a novel role for common γc cytokines in combination with donor APCs in the expansion of donor-specific CD8(+)CD28(-) T suppressor cells, and represent a robust strategy for in vitro generation of such cells for adoptive cellular immunotherapy in transplantation.
    Full-text · Article · Dec 2011 · PLoS ONE
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    ABSTRACT: As the knowledge of CD4+CD25bright+FoxP3+ regulatory T cells in experimental transplant models grows, we need to understand how and to what extent these suppressor cells regulate donor-directed immune events in the transplantation clinic. This review focuses on the function of regulatory T cells in the peripheral blood and the transplanted organ of patients after heart transplantation during immunological quiescence and rejection. Here, we present data that peripheral CD4+CD25bright+FoxP3+ T cells of heart transplant patients who experience acute rejection have inadequate immune regulatory function in vitro compared with those of nonrejecting patients. During rejection, potent donor-specific T-cell suppressors are present in the transplanted organ. The studies in transplant patients' show that the function of CD4+CD25bright+FoxP3+ regulatory T cells in alloimmunity is to inhibit the activation of effector T cells, to prevent rejection, and to control the antidonor response at the graft itself at later stages of immune reactivity.
    No preview · Article · Aug 2009 · Current opinion in organ transplantation
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    Full-text · Article · Jul 2010 · Transplantation
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