ADMINISTRATION OF NONCYTOLYTIC IL-10 FC IN MURINE MODELS OF LIPOPOLYSACCHARIDE-INDUCED SEPTIC SHOCK AND ALLOGENEIC ISLET TRANSPLANTATION/

Numerous studies have suggested the potential application of IL-10 as an anti-inflammatory and as an antirejection agent. Unfortunately, cyt okines have short circulating t(1/2) We developed a murine IL-10/Fc ga mma 2a immunoligand that possesses the biologic functions of IL-10 and the long circulating t(1/2) in vivo, characteristic of Igs. We mutate d the Fc gamma 2a fragment to render the immunoligand ineffective in d irecting Ab-dependent cell-mediated cytotoxicity and complement-direct ed cytolysis (noncytolytic IL-10/Fc(IL-10/Fc(2-))). In terms of IL-10 activity, IL-10/Fc(2-) was as effective as rIL-10 mole per mole in pre venting lethal septic shock, but the immunoligand had a prolonged peri od of efficacy in accord with its extended circulating half-life. Cont rary to expectations, IL-10/Fc(2-) treatment tended to accelerate the destruction of islet cell allografts and increase the levels of granzy me B gene expression in local draining lymph nodes. These data suggest that the enhanced cytotoxic activity of allograft-destroying CTLs may contribute to the accelerated allograft rejection. Finally, our studi es suggest that a noncytolytic IL-10/Fc fusion protein provides a usef ul tool to study the biologic effects of IL-10 in vivo and may provide a useful agent for the prevention and treatment of septic shock.