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, cytokines have short circulating t1/2 We developed a murine IL-10/Fc gamma 2a immunoligand that possesses the biologic functions of IL-10 and the long circulating t1/2 in vivo, characteristic of Igs. We mutated the Fc gamma 2a fragment to render the immunoligand ineffective in directing Ab-dependent cell-mediated cytotoxicity and complement-directed cytolysis (noncytolytic IL-10/Fc (IL-10/Fc2-)). In terms of IL-10 activity, IL-10/Fc2- was as effective as rIL-10 mole per mole in preventing lethal septic shock, but the immunoligand had a prolonged period of efficacy in accord with its extended circulating half-life. Contrary to expectations, IL-10/Fc2- treatment tended to accelerate the destruction of islet cell allografts and increase the levels of granzyme 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 studies suggest that a noncytolytic IL-10/Fc fusion protein provides a useful 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.
Zheng
X X
XX
Harvard Medical School, Department of Medicine, Boston, MA, USA.
Steele
A W
AW
Nickerson
P W
PW
Steurer
W
W
Steiger
J
J
Strom
T B
TB
D000818:Animals; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012772:Shock, Septic / Q000276:immunology / Q000628:therapy*
D007141:Immunoglobulin Fc Fragments; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10