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To investigate the antigen specificity of regulatory T cells capable of preventing transplant rejection, we have developed two different strategies to achieve tolerance to fully mismatched skin grafts in euthymic mice. A combination of nondepleting Abs targeting CD4, CD8, and CD154 (CD40 ligand) induces dominant transplantation tolerance to fully mismatched skin allografts. Such tolerance is antigen-specific, mediated by regulatory T ceils, and can be extended through linked suppression to naive lymphocytes. The same protocol, when combined with allogeneic bone marrow, enables the development of mixed hematopoietic chimerism and deletional tolerance. Although we cannot exclude that some regulatory T cells may persist in chimeric mice, these cells are insufficient to mediate linked suppression. [CD4.sup.+][CD25.sup.+] T cells, whether taken from naive mice or from mice tolerized through either treatment protocol, were always able to prevent rejection of skin grafts by naive [CD4.sup.+] T cells, and did so with no demonstrable specificity for the tolerizing donor antigens. Such data question whether [CD4.sup.+][CD25.sup.+] regulatory T cells alone can account for the antigen specificity of dominant transplantation tolerance.

Various types of T cells with heterogeneous receptors are found in the inflammatory infiltrate in the central nervous system after experimental encephalomyelitis is induced with a T-cell clone L10C1. This clone responds to the myelin basic protein epitope p87-99. It is shown that in vivo tolerization of L10C1 with an analogue of p87-99 reverses established paralysis, reduces inflammatory infiltrates and eliminates the heterogeneous T-cell infiltrate from the brain..

Abstract Background A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. Results We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. Conclusion We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.