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Cyclosporine: A New and Promising Immunosuppressive Agent
188
TRANSPLANTATION
irradiation to prospective renal allograft recipients. The radiation dose required to prolong allograft survival produced such severe bone marrow and other toxicities that this approach was all but abandoned by the mid 1960s. Since then, various attempts have been made to direct radiation specifically at immunocompetent lymphoid cells, including local graft irradiation, intralymphatic or intravenous administration of radioisotopes that are specific for lymphatic tissue and extracorporeal irradiation of blood and lymph. The radiation dose delivered by these techniques is difficult to control, the effect on allograft survival is variable and clinical application has been limited. Total lymphoid irradiation has been used to treat Hodgkin's disease for >20 years. Animal experiments have shown that total lymphoid irradiation impaired the ability of rodents to reject organ allografts. If donor-strain bone marrow was administered after total lymphoid irradiation, chimerism without graft-versus-host disease and permanent acceptance of the allograft were possible, although some investigators observed graft-versus-host disease in recipients of bone marrow treated with total lymphoid irradiation. Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation then after but when used after transplantation it can be combined with pharmacologic immunosuppression to achieve a positive effect. Recently, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably and, thus, the impetus to use total lymphoid irradiation for its immunosuppressive effect alone is less compelling. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated or nearly eliminated altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen. W. W. K. 1 figure, 1 table, 49 references
Immunologic Monitoring of the Renal Transplant Recipient
M. SUTHANTHIRAN AND M. R. GAROVOY, Transplant lmmunobiochemistry Laboratory, Rogosin Kidney Center, The New York Hospital-Cornell Medical Center, and Departments of Medicine, Surgery and Biochemistry, Cornell University Medical College, New York, New York and Immunogenetics and Transplantation Laboratory, and Departments of Surgery and Medicine, University of California, San Francisco, California
as a decrease in glomerular filtration rate, with the hope that earlier therapeutic interventions will result in better salvage rates of grafts undergoing rejection, 2) identification of immune events that would corroborate a histologic basis for renal dysc function, thereby providing reliable noninvasive diagnostic indexes for graft rejection, 3) prediction of reversibility of a given rejection episode, and 4) individualization of specific and nonspecific immunosuppressive therapy currently in use. At best, immune monitoring is the result of a successful marriage of basic and applied research in the area of transplantation biology. Individualization of immune therapy and specific modulation of immune responses, the cherished goals of the transplant clinician, can be expected in the near future. W. W. K. 1 figure, 5 tables, 79 references
Cyclosporine: A New and Promising Immunosuppressive Agent
Department of Surgery, Divisions of Urology and Immunology and Organ Transplantation, The University of Texas Medical School, Houston, Texas
S. M. FLECHNER,
Urol. Clin. N. Amer., 10: 263-275 (May) 1983 Cyclosporine (formerly cyclosporin A) is a new, potent immunosuppressive agent that has been shown to ameliorate allograft survival in animal and human studies. Cyclosporine induces a potent, reversible and preferential suppression of T lymphocytes without attendant myelosuppression. This exciting new agent no doubt will be a major contributor in the 1980s to the quest for universal acceptance of human organ allografts. Prevailing evidence is that cyclosporine acts early and reversibly on the triggering mechanism of lymphocyte proliferation, rather than interrupting the stimulation or processing of antigen. The major concern about its widespread clinical use has been the observed nephrotoxicity and possible development of lymphomas in treated patients. Adverse side effects may be minimized by pharmacologic monitoring of drug levels. Future questions include the ideal dosage schedule necessary for additional immunosuppressive agents, distinction between nephrotoxicity and rejection, and the precise mode of absorption, accumulation and metabolism of the drug. Cyclosporine may be considered the prototype of a new generation of immunosuppressive agents that open new perspectives in the field of immunoregulation. The ability to synthesize the compound may permit future biochemical manipulations to increase the immunobiologic specificity and decrease the toxicity of the drug. W. W. K. 5 figures, 2 tables, 101 references
Urol. Clin. N. Amer., 10: 315-325 (May) 1983
Procurement and Preservation of Cadaver Kidneys
The most common complication in recipients of renal grafts is rejection, which fortunately is limited and reversible. The fact that graft rejection is secondary to multiple immune assault mechanisms has provided the impetus and rationale for the development of a variety of techniques to detect pertinent immune effector mechanisms. Because graft compromise results from a complex interplay of cellular and humoral immune responses successful monitoring of graft recipients is accomplished with the aid of a battery of assays. Therefore, a single ideal immune test for rejection cannot exist. Immunologic monitoring of renal transplant recipients includes 1) delineation of immune events antedating functional alterations, such
J. M. BARRY, Departments of Surgery, Urology and Renal
Transplantation, Oregon Health Sciences University, Portland, Oregon Urol. Clin. N. Amer., 10: 205-216 (May) 1983 Improved patient survivals after failed kidney transplants, increasing cadaver kidney transplantation in high risk patients and the reluctance of transplant teams to use a kidney from a living related donor unless graft success can be assured reasonably have resulted in an increasing need for cadaver kidneys. Although brain death legislation, public and professional education, kidney sharing among transplant centers and health
TRANSPLANTATION
irradiation to prospective renal allograft recipients. The radiation dose required to prolong allograft survival produced such severe bone marrow and other toxicities that this approach was all but abandoned by the mid 1960s. Since then, various attempts have been made to direct radiation specifically at immunocompetent lymphoid cells, including local graft irradiation, intralymphatic or intravenous administration of radioisotopes that are specific for lymphatic tissue and extracorporeal irradiation of blood and lymph. The radiation dose delivered by these techniques is difficult to control, the effect on allograft survival is variable and clinical application has been limited. Total lymphoid irradiation has been used to treat Hodgkin's disease for >20 years. Animal experiments have shown that total lymphoid irradiation impaired the ability of rodents to reject organ allografts. If donor-strain bone marrow was administered after total lymphoid irradiation, chimerism without graft-versus-host disease and permanent acceptance of the allograft were possible, although some investigators observed graft-versus-host disease in recipients of bone marrow treated with total lymphoid irradiation. Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation then after but when used after transplantation it can be combined with pharmacologic immunosuppression to achieve a positive effect. Recently, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably and, thus, the impetus to use total lymphoid irradiation for its immunosuppressive effect alone is less compelling. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated or nearly eliminated altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen. W. W. K. 1 figure, 1 table, 49 references
Immunologic Monitoring of the Renal Transplant Recipient
M. SUTHANTHIRAN AND M. R. GAROVOY, Transplant lmmunobiochemistry Laboratory, Rogosin Kidney Center, The New York Hospital-Cornell Medical Center, and Departments of Medicine, Surgery and Biochemistry, Cornell University Medical College, New York, New York and Immunogenetics and Transplantation Laboratory, and Departments of Surgery and Medicine, University of California, San Francisco, California
as a decrease in glomerular filtration rate, with the hope that earlier therapeutic interventions will result in better salvage rates of grafts undergoing rejection, 2) identification of immune events that would corroborate a histologic basis for renal dysc function, thereby providing reliable noninvasive diagnostic indexes for graft rejection, 3) prediction of reversibility of a given rejection episode, and 4) individualization of specific and nonspecific immunosuppressive therapy currently in use. At best, immune monitoring is the result of a successful marriage of basic and applied research in the area of transplantation biology. Individualization of immune therapy and specific modulation of immune responses, the cherished goals of the transplant clinician, can be expected in the near future. W. W. K. 1 figure, 5 tables, 79 references
Cyclosporine: A New and Promising Immunosuppressive Agent
Department of Surgery, Divisions of Urology and Immunology and Organ Transplantation, The University of Texas Medical School, Houston, Texas
S. M. FLECHNER,
Urol. Clin. N. Amer., 10: 263-275 (May) 1983 Cyclosporine (formerly cyclosporin A) is a new, potent immunosuppressive agent that has been shown to ameliorate allograft survival in animal and human studies. Cyclosporine induces a potent, reversible and preferential suppression of T lymphocytes without attendant myelosuppression. This exciting new agent no doubt will be a major contributor in the 1980s to the quest for universal acceptance of human organ allografts. Prevailing evidence is that cyclosporine acts early and reversibly on the triggering mechanism of lymphocyte proliferation, rather than interrupting the stimulation or processing of antigen. The major concern about its widespread clinical use has been the observed nephrotoxicity and possible development of lymphomas in treated patients. Adverse side effects may be minimized by pharmacologic monitoring of drug levels. Future questions include the ideal dosage schedule necessary for additional immunosuppressive agents, distinction between nephrotoxicity and rejection, and the precise mode of absorption, accumulation and metabolism of the drug. Cyclosporine may be considered the prototype of a new generation of immunosuppressive agents that open new perspectives in the field of immunoregulation. The ability to synthesize the compound may permit future biochemical manipulations to increase the immunobiologic specificity and decrease the toxicity of the drug. W. W. K. 5 figures, 2 tables, 101 references
Urol. Clin. N. Amer., 10: 315-325 (May) 1983
Procurement and Preservation of Cadaver Kidneys
The most common complication in recipients of renal grafts is rejection, which fortunately is limited and reversible. The fact that graft rejection is secondary to multiple immune assault mechanisms has provided the impetus and rationale for the development of a variety of techniques to detect pertinent immune effector mechanisms. Because graft compromise results from a complex interplay of cellular and humoral immune responses successful monitoring of graft recipients is accomplished with the aid of a battery of assays. Therefore, a single ideal immune test for rejection cannot exist. Immunologic monitoring of renal transplant recipients includes 1) delineation of immune events antedating functional alterations, such
J. M. BARRY, Departments of Surgery, Urology and Renal
Transplantation, Oregon Health Sciences University, Portland, Oregon Urol. Clin. N. Amer., 10: 205-216 (May) 1983 Improved patient survivals after failed kidney transplants, increasing cadaver kidney transplantation in high risk patients and the reluctance of transplant teams to use a kidney from a living related donor unless graft success can be assured reasonably have resulted in an increasing need for cadaver kidneys. Although brain death legislation, public and professional education, kidney sharing among transplant centers and health