The metalloproteinase-mediated pathway is essential for generation of soluble HLA class I proteins by activated cells in vitro:: Proposed mechanism for soluble HLA release in transplant rejection

We and others have found donor-derived soluble beta(2)m-associated HLA class I proteins (sHLA/beta(2)m) in the serum of allograft recipients with acute and chronic rejection. Whether appearance of sHLA/beta(2)m and upregulated expression of donor cell-bound HLA/beta(2)m during allograft rejection are related events is unknown. Activation-induced upregulation of in vitro HLA/beta(2)m expression correlates with the surface expression of another form of HLA class I, namely beta(2)m-free HLA heavy chains (beta(2)m-free HC). We have shown that beta(2)m-free HC, bur nor beta(2)m-associated HC, are then cleaved by a specific mem brane-bound metalloproteinase and released into supernatants as soluble 36 kDa proteins. We show now that activated peripheral blood lymphocytes produce predominantly the 36 kDa form of sHLA proteins which is present in supernatants as both beta(2)m-free HC and sHLA/ beta(2)m Importantly, the metalloprotease inhibitor BB-94 blocked not only the release of soluble beta(2)m-free HC, but also the appearance of sHLA/beta(2)m in cell supernatants. LON. levels of 36 kDa beta(2)m-free HC were also present in human plasma of healthy donors. These data suggest an important role for the HLA class I-specific metalloproteinase in vivo in healthy individuals and during allograft rejection in the generation of soluble beta(2)m-free and beta(2)m-associated HLA proteins. Human Immunology 59: 426-434 (1998). (C) American Society for Histocompatibility and Immunogenetics, 1998. Published by Elsevier Science Inc.