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Bcl-2
protection of islet allografts is unmasked by costimulation blockade
R.M. Sutherland,
J. L. Brady, A.M. Lew, in collaboration with J. Allison, Department
of Microbiology and Immunology, University of Melbourne; H.E. Thomas
and T.W.H. Kay, St. Vincent’s Institute of Medical Research, Melbourne
Pancreatic islet
transplantation may cure type 1 diabetes but there are insufficient
islet donors. Furthermore, side-effects of immunosuppressive drugs preclude
transplants into patients whose diabetes is controlled by parenteral
insulin. We hypothesised that overexpressing anti-apoptotic Bcl-2 or
secretion of immunomodulatory CTLA4Ig molecules in islet beta cells
would enhance survival of transplanted islets whilst minimizing systemic
side-effects. Although Bcl-2 overexpression alone was insufficient in
protecting mouse islet allografts from rejection, its beneficence was
shown by enhanced protection when the adaptive immune response was inhibited
by locally produced CTLA4Ig. Thus, combined anti-apoptotic and immunosuppressive
intervention may reduce the level of systemic immunosuppression or quantity
of donor tissue required.
Activated
macrophages require T cells for traffic to transplant tissues
Y. Zhan,
J. L. Brady, A.M. Lew, in collaboration with W. Irawaty, H.E. Thomas
and T.W.H. Kay, St. Vincent’s Institute of Medical Research, Melbourne
Although macrophage activation
by T cells is critical for the xenograft rejection, we found that activated
macrophages in the absence of T cells were unable to reject xenografts
under the kidney capsule, although they rejected xenogeneic cells in
the peritoneal cavity (with an abundance of resident macrophages). This
implies that activated macrophages self-recruit inefficiently to peripheral
graft sites. T-cell transfer resulted in the rejection of xenogeneic
cells at both the kidney capsule and peritoneal sites. These results
argue that activated macrophages (as the result of T-cell activation)
still require T cells for xenograft rejection at peripheral sites.
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