Regulatory T-cells in Therapeutic Transplantation Tolerance
Rodent studies have shown that transplantation tolerance can be achieved with short courses of therapeutic intervention with monoclonal antibodies, without the need for hemopoietic chimerism. This was first established by us using non-lytic antibody treatment directed to the co-receptors CD4 and CD8, but was later also demonstrated using antibodies to directed to co-stimulatory molecules such as CD154. Tolerance induced by these methods need not delete nor inactivate all alloreactive cells, but involves the induction, recruitment and expansion of CD4 regulatory T-cells (Treg). This includes both natural and “induced” CD4+CD25+ FoxP3+ Treg, but other forms of regulatory T-cell may also participate. The induction of therapeutic tolerance requires TGFβ, which not only raises the threshold for T-cell responses, but is also required for the conversion of naive T-cells to Treg. Treg can be found in tolerated grafts as can T-cells competent to reject. Elimination of Treg from the graft can precipitate rejection, suggesting that graft-resident T-reg confer some form of privilege onto the tissue. This is consistent with our earlier interpretation of linked-suppression where we hypothesised that antigen-bearing APC bring Treg into microenvironments that prevent damaging immune responses. Persisting antigen from accepted grafts is processed as if “self” antigen by quiescent host APC, and this antigen-source is sufficient to maintain T-cell unresponsiveness and recruit further Treg into the process. In this way, cohorts of new regulatory T-cells are generated through the life of the graft, through “infectious tolerance”. There is compelling data that Treg act not only in the induction phase, but also at later stages of the rejection response.
KeywordsTransplantation Tolerance FoxP3 mRNA Altered Peptide Ligand Donor Antigen Infectious Tolerance
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