Abstract
Cyclosporine A (CsA) is a fungus-derived molecule with potent immunosuppressive activity that has been largely used to downregulate cell-mediated immune responses during transplantation. However, previous data have indicated that CsA shows immunomodulatory activity that relays on the antigen concentration and the dose of CsA used. To test the hypothesis that minimal doses of CsA may show different outcomes on grafts, we used an experimental model for skin transplants in mice. ICR outbred mice received skin allografts and were either treated daily with different doses of CsA or left untreated. Untreated mice showed allograft rejection within 14 days, with graft necrosis, infiltration of neutrophils and macrophages and displayed high percentages of CD8+ T cells in the spleens, which were associated with high serum levels of IL-12, IFN-γ and TNF-α. As expected, mice treated with therapeutic doses of CsA (15 mg/kg) did not show allograft rejection within the follow-up period of 30 days and displayed the lowest levels of IL-12, IFN-γ and TNF-α as well as a reduction in CD8+ lymphocytes. In contrast, mice treated with consecutive minimal doses of CsA (5 × 10−55 mg/kg) displayed an acute graft rejection as early as one to five days after skin allograft; they also displayed necrosis and strong inflammatory infiltration that was associated with high levels of IL-12, IFN-γ and TNF-α. Moreover, the CD4+ CD25hiFoxP3+ subpopulation of cells in the spleens of these mice was significantly inhibited compared with animals that received the therapeutic treatment of CsA and those treated with placebo. Our data suggest that consecutive, minimal doses of CsA may affect Treg cells and may stimulate innate immunity.
Highlights
When allograft tissues differ from the host at class I and class II loci, CD8+ T cells are activated through recognition of the graft alloantigens
Differentiation of cytotoxic T lymphocytes (CTLs) is generally regulated by CD4+ T cells, which are stimulated by antigen-presenting cell (APC) class II
In an attempt to dissect the mechanisms that lead to immune modulation in response to Cyclosporine A (CsA) treatment, we examined the role of consecutive low doses of CsA in mice receiving an allograft skin transplant
Summary
When allograft tissues differ from the host at class I and class II loci, CD8+ T cells are activated through recognition of the graft alloantigens. In contrast to other cytotoxic immune suppressors, CsA does not kill immune effector cells but rather selectively inhibits their proliferative activation and expansion, mainly by interfering with IL-2 synthesis. This unique suppressive activity of CsA was first challenged by Bretscher and Havele [10], who found that CsA used in low doses together with a specific antigen could bias a humoral immune response toward a cell-mediated immune response or vice versa, depending on the concentrations of the inducing antigen and CsA [10]. CsA appears to play a more sensitive role in modulating the immune response
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