PROLONGATION OF SKIN ALLOGRAFTS BY RECOMBINANT TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1

Objective The hypothesis is that systemic administration of recombinan t tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleuk in-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft . Summary Background Data Tumor necrosis factor and IL-1 are pluripote nt cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced b y systemic administration of recombinant cytokines. The authors previo usly have demonstrated that pretreatment with cytokines such as IL-1 o r TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram -negative sepsis, cancer cachexia, and oxygen toxicity. Methods Skin g rafts from the tails of Balb/c mice were placed on the backs of C57B1/ 6 mice. Mice were treated with daily intraperitoneal saline, recombina nt m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoc he, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necros is factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kapl an-Meier plot and analyzed by the log-rank test. Comparison of proport ions was done using the Fisher's exact test. Results Either TNF or IL- 1 alone significantly prolonged skin graft survival compared with sali ne control, Furthermore, the combination of TNF and IL-1 prolonged ski n graft survival longer than either cytokine alone. Mice on the highes t dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cyto kine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1. Conclusion Bo th TNF and IL-1 can be effective as suppressors of skin allograft reje ction in mice.