IL-10/Fc inhibits macrophage function and prolongs pancreatic islet xenograft survival.
BACKGROUND
Xenograft rejection is a complex response in which macrophages and other effector cells are activated by CD4+ T cells. Initiation and regulation of this response is in part mediated by cytokines. In this study we test the hypothesis that xenograft destruction is an interleukin- (IL) 10 responsive, macrophage-mediated event.


METHODS
To study the effect of the systemic administration of IL-10 on pancreatic islet xenograft rejection, a fusion protein of IL-10/Fc was used. This immunoligand possesses the bioavailability of IL-10 and the long circulating t1/2 in vivo, characteristic of Ig. Wistar rat islets were transplanted into C57BL6 mice. IL-10/Fc was administered either immediately before transplantation or in the posttransplant period.


RESULTS
Both therapeutic protocols prolonged xenograft survival. Macrophage effector function was reduced in IL-10/Fc-treated mice, with a reduced macrophage infiltrate, reduced IL-12 and tumor necrosis factor-alpha gene expression and reduced serum NO2- levels. Although the number of T cells infiltrating islet grafts was not reduced, T cell effector function was inhibited in IL-10/Fc-treated animals with reduced interferon-gamma and IL-4 gene expression, reduced anti-donor cytotoxicity by recipient splenocytes and reduced anti-donor IgG1 antibody production. Ultimate rejection of the xenografts appears to be mediated by a CD4+ T cell dependent mechanism probably as a result of inadequate inhibition of IL-12 production by macrophages.


CONCLUSIONS
IL-10/Fc prolonged rat pancreatic islet xenograft survival by inhibiting macrophage mediated immune responses. The effectiveness of this agent when administered pretransplant suggests it may have a role as an induction agent with potential clinical application.
Feng
X
X
National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, NSW, Australia.
Zheng
X X
XX
Yi
S
S
Lehnert
A M
AM
Strom
T B
TB
O'Connell
P J
PJ
D000818:Animals; D000910:Antibodies, Heterophile / Q000032:analysis; D015870:Gene Expression / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D007074:Immunoglobulin G / Q000032:analysis; D016753:Interleukin-10 / Q000235:genetics*; D016381:Islets of Langerhans Transplantation; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D014183:Transplantation, Heterologous
D000910:Antibodies, Heterophile; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10