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8.7-02 Effects of human prolactin on human lymphocyte proliferation and cyclosporin a immunosuppression
Abstracts
8.7 '-02
EFFECTS OF HUMAN PROLACTIN ON HUMAN LYMPHOCYTE PROLIFERATION AND CYCLOSPORIN A IMMUNOSUPPRESSION.Patty Bakkestad-Leeare, Peter Nickerson, Rachel McKenna, John Jeffery, David Rush, Transplant Program and Department of Medicine, University of Manitoba, Canada. Prolactin (PRL) is required for optimal lymphocyte proliferation in experimental animals, and it has been suggested that cyclosporin A (CSA) may exert its' immunosuppressive effect by blocking a T-lymphocyte PRL receptor. A biphasic effect of PRL on lymphocyte functions has also been reported. The effects of human PRL on human lymphocyte proliferation and CSA immunomodulation have not bee 1) Human PRL (lo-s-~~~Y~~~s~~y~~~~~~~~.r~~,, ;p"$3F M) neither stimulated nor inhibited the human MLR, and had no effect on PHA, Con-A or PMA stimulated human lymphocyte mitogenesis as compared to Human Ser-urn Albumin control; 2) The inhibitory effects of CSA (1C and lOOng/ml) on PHA-stimulated lyyphocyte mitogenesis was not affected by PRL (up to 10 M); 3) The PRLdependent proliferation of the Nb-2 lymphoma cell line was not inhibited by CSA or a major CSA metabolite (M17) (l-lOOOng/ml for each); 4) Binding of 3H-CSA to to the Jurkat T cell line was not ~Y~~~e~yb"F"~~"trsOoflll PRL). These results suggest that human PRL has no immunomodulating effect on human lymphocytes in vitro, and that CSA does not exert its'immunosuppressive effect via the blocking of a lymphocyte PRL receptor.
8.7-03
CYCLOSPORINE I'fETAEiOLITES IN IMMUNOSUPPRESSION AND NEPHROTOXICITY. Thomas G. Rosano, Neil Lempert, and Brian Freed, Albany Medical Center, Albany, New York 12208 Cyclosporine (CsA) is a potent immunosuppressive agent that is metabolized extensively by humans. The process of metabolism decreases the immunosuppressive activity of the compound. Thus, mono-hydroxylated metabolites (Ml7 and Ml) are less immunosuppressive than CsA and the dihydroxylated M8 is essentially inactive. However, very little is known about the contribution of these cyclosporines to nephrotoxicity. We studies the distribution of CsA and its metabolites in 28 renal allograft recipients treated with CsA, azathioprine, and steroids. CsA and the major metabolites (Ml and M17) comprised over 96% of the total cyclosporines in the blood in patients with good renal function. In addition, there was no significant change the amount or distribution of CsA and these metabolites during episodes of rejection. However, in two patients with episodes of nephrotoxicity, there appeared a significant rise in the amount of polar metabolites in the blood. These metabolites, which co-elute with M8 on HPLC, disappeared as soon as the dose of CsA was decreased. We hypothesize that the metabolism of CsA decreases its immunosuppressive properties while increasing its nephrotoxic properties and have begun a clinical trial to investigate the correlation between nephrotoxicity and the appearance of this metabolite.
8.7 '-02
EFFECTS OF HUMAN PROLACTIN ON HUMAN LYMPHOCYTE PROLIFERATION AND CYCLOSPORIN A IMMUNOSUPPRESSION.Patty Bakkestad-Leeare, Peter Nickerson, Rachel McKenna, John Jeffery, David Rush, Transplant Program and Department of Medicine, University of Manitoba, Canada. Prolactin (PRL) is required for optimal lymphocyte proliferation in experimental animals, and it has been suggested that cyclosporin A (CSA) may exert its' immunosuppressive effect by blocking a T-lymphocyte PRL receptor. A biphasic effect of PRL on lymphocyte functions has also been reported. The effects of human PRL on human lymphocyte proliferation and CSA immunomodulation have not bee 1) Human PRL (lo-s-~~~Y~~~s~~y~~~~~~~~.r~~,, ;p"$3F M) neither stimulated nor inhibited the human MLR, and had no effect on PHA, Con-A or PMA stimulated human lymphocyte mitogenesis as compared to Human Ser-urn Albumin control; 2) The inhibitory effects of CSA (1C and lOOng/ml) on PHA-stimulated lyyphocyte mitogenesis was not affected by PRL (up to 10 M); 3) The PRLdependent proliferation of the Nb-2 lymphoma cell line was not inhibited by CSA or a major CSA metabolite (M17) (l-lOOOng/ml for each); 4) Binding of 3H-CSA to to the Jurkat T cell line was not ~Y~~~e~yb"F"~~"trsOoflll PRL). These results suggest that human PRL has no immunomodulating effect on human lymphocytes in vitro, and that CSA does not exert its'immunosuppressive effect via the blocking of a lymphocyte PRL receptor.
8.7-03
CYCLOSPORINE I'fETAEiOLITES IN IMMUNOSUPPRESSION AND NEPHROTOXICITY. Thomas G. Rosano, Neil Lempert, and Brian Freed, Albany Medical Center, Albany, New York 12208 Cyclosporine (CsA) is a potent immunosuppressive agent that is metabolized extensively by humans. The process of metabolism decreases the immunosuppressive activity of the compound. Thus, mono-hydroxylated metabolites (Ml7 and Ml) are less immunosuppressive than CsA and the dihydroxylated M8 is essentially inactive. However, very little is known about the contribution of these cyclosporines to nephrotoxicity. We studies the distribution of CsA and its metabolites in 28 renal allograft recipients treated with CsA, azathioprine, and steroids. CsA and the major metabolites (Ml and M17) comprised over 96% of the total cyclosporines in the blood in patients with good renal function. In addition, there was no significant change the amount or distribution of CsA and these metabolites during episodes of rejection. However, in two patients with episodes of nephrotoxicity, there appeared a significant rise in the amount of polar metabolites in the blood. These metabolites, which co-elute with M8 on HPLC, disappeared as soon as the dose of CsA was decreased. We hypothesize that the metabolism of CsA decreases its immunosuppressive properties while increasing its nephrotoxic properties and have begun a clinical trial to investigate the correlation between nephrotoxicity and the appearance of this metabolite.