Elsevier

Transplantation Proceedings

Volume 33, Issues 1–2, February–March 2001, Pages 1754-1756
Transplantation Proceedings

Bone marrow transplantation
Autoreactive T-Cell subsets in acute and chronic syngeneic graft-versus-host disease

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Induction of syngeneic GVHD and isolation of autoreactive T-Cell clones

The induction of syngeneic GVHD in Lewis rats has been extensively detailed elsewhere.2 Autoreactive T-cell clones were established from limiting dilution cultures of peripheral blood lymphocytes, lymph node cells and splenic T cells harvested from animals with biopsy-confirmed syngeneic GVHD as previously described.3, 4 The in vitro specificity of the effector T cells was defined using an [3H]-thymidine based assay to measure their ability to kill target cells loaded with truncated variants of

Results and discussion

The induction of a severe autoaggression syndrome resembling acute and chronic GVHD by administering CsA after autologous or syngeneic BMT certainly remains an enigma. In large part, the induction of syngeneic GVHD is due to the ability of CsA to inhibit the thymic-dependent clonal deletion of autoreactive T cells.1 The failure to delete autoreactive T cells, however, is insufficient by itself to allow for the induction of autoaggression in this model. The elimination of a peripheral regulatory

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References (5)

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    This might not only result in an increased pool of CD4+CD45RA+CD31+ T cells with low-affinity, self-reacting TCR [18], but also to escape of autoreactive T cells. Their expansion may cause further activation of effector functions, including cytokine secretion, cytolytic activity, and antibody production due to B cell activation and hyper-reactivity, resulting in clinically noticeable organ damage [52]. In our study, CD19+CD21low B cells and CD4+CD45RA+CD31+ T cells assessed on day 100 after HCT significantly predicted later development of cGVHD independently of clinical parameters.

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    cGVHD is caused by alloreactive T cells transferred into the recipient along with hematopoietic stem cells and autoreactive T cells developed after ASCT [1]. New theories suggest that impaired thymic function with defective immune reconstitution may contribute to cGVHD [2,3] by a defective peripheral immune regulation, cytokine dysregulation [4,5] and a succeeding imbalance in the so-called T helper cell 1/2-cytokine secretion pathways [1,6–8]. In this context, cGVHD has been associated with an activation of the T helper cell 2 (Th2) pathway where certain Th2 cytokines, e.g. interleukin (IL)-5, also act as potent eosinophilopoietic factors [7].

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    However, it now also appears that, to achieve transplant tolerance, a mixed microchimerism between donor organ and recipient has to be established, with donor cells entering the recipient and recipient immune cells entering the donor organ, at times resulting in GVHD, characterized by the formation of autoantibodies in the host.37 Animal experiments suggest that chronic GVHD may be mediated primarily by the donor’s T cells, which respond to antigens shared by donor and host.38-39 This model appears particularly relevant to pregnancy.

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  • Chronic graft-versus-host disease

    2003, Biology of Blood and Marrow Transplantation
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    The etiologic contribution of alloreactive T cells to the development of chronic GVHD is supported by the observation that T-cell depletion is associated with less chronic GVHD in HLA-matched sibling marrow transplantation [21], whereas peripheral blood stem cell (PBSC) transplantation [22-29] and donor lymphocyte infusions (DLI) are associated with higher rates of chronic GVHD [30,31]. Autoreactive T cells have been implicated in the pathogenesis of cyclosporine-induced autologous GVHD, which clinically resembles allogeneic chronic GVHD but is mediated by autoreactive T cells that recognize the CLIP region of major histocompatibility complex class II molecules [32]. Cyclosporine (CSA) inhibits thymic-dependent clonal deletion of autoreactive T cells, thereby paradoxically disrupting self-tolerance.

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Supported by grants AI 24319 and CA15396 from the National Institutes of Health.

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