Deoxyspergualin is a unique immunosuppressive agent with selective utility in inducing tolerance to pancreas islet xenografts.
Recent studies of DSG have demonstrated that this agent has a unique ability among immunosuppressive drugs to induce long-term survival and functional tolerance of discordant islet xenografts from pig to the Lewis rat. In addition, DSG was found to be nontoxic to islet cells in culture and without any inhibitory effect upon insulin secretion in contrast to azathioprine, FK 506, and CyA. The long-term functional tolerance seen with these islets appears to involve a stable block of antidonor humoral immunity, although more testing is necessary to characterize the precise state producing functional tolerance in this model. Other studies presented at this meeting demonstrate the ability of DSG and RATG immunosuppression to produce long-term discordant islet survival in the NOD mouse, which suffers from a virulent autoimmune condition that destroys transplanted islets in most NOD models shortly after transplantation, even when the islets are microencapsulated. The functional tolerance is especially difficult to achieve with a discordant xenograft and thus the ability of RATG and DSG to achieve this impressive. Long-term studies using DSG and total lymphoid irradiation suggest that RATG is not essential to long-term survival but clearly it is quite synergistic with DSG and also has the advantage of being nontoxic. In fact, all animals receiving the DSG/RATG therapy were essentially free of toxicity and no deaths were observed that could be attributed to the drug therapy. This short-term course of administration of the drugs helped achieve this lack of toxicity. The high levels of synergism of ATG in this model could be related to the numerous monoclonal reactivities seen in polyclonal ATG with demonstrated titers of 1 to 4000 or greater for a number of specificities associated with B cells and macrophages, which could well be contributing to the block of humoral antibody previously demonstrated in DSG/RATG treated animals. The DSG, however, is especially effective in synergizing an antihumoral antibody response and can be shown to result in a striking decrease in early humoral antibody production following transplantation. Overall, these studies demonstrate a high potential of this immunosuppressive therapy to promote long-term discordant islet xenograft survival and functional tolerance without chronic rejection or the islet toxicity common to the currently used immunosuppressive agent. DSG may have a wide potential utility in islet transplantation but it appears to have its strongest effect in islet xenografting.
Thomas
F
F
East Carolina University School of Medicine/University Medical Center, Greenville, NC 27858.
Pittman
K
K
Ljung
T
T
Cekada
E
E
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival; D006146:Guanidines / Q000627:therapeutic use*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation; D007328:Insulin / Q000032:analysis; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology / Q000502:physiology
D001786:Blood Glucose; D006146:Guanidines; D007166:Immunosuppressive Agents; D007328:Insulin; C037258:gusperimus