2-Chlorodeoxyadenosine in combination with cyclosporine inhibits the development of transplant arteriosclerosis in rat cardiac allografts

2-Chlorodeoxyadenosine in combination with cyclosporine inhibits the development of transplant... ELSEVIER 2Ghlorodeoxyadenosine in Combination With Cyclosporine Inhibits the Development of Transplant Arteriosclerosis in Rat Cardiac Allografts D.V. Cramer, G.D. Wu, F.A. Chapman, C. Marboe, and DR. Salomon ONG-TERM SURVIVAL following organ transplantation has been associated with a high frequency of vascular disease (transplant arteriosclerosis, TA) in the muscular arteries of the donor graft. It is estimated that approximately 50% of heart graft recipients have evidence of coronary vascular disease 5 years following transplantation.’ The prevention of TA may depend on the development of more effective immunosuppression to prevent or treat chronic rejection without increasing the risk of adverse side effects. We have recently used a rat cardiac allograft model to evaluate an antitumor agent, 2-chlorodeoxyadenosine (2-CdA) in the prevention of TA. METHODS ducer cells, were reduced by 60% at 14 and 70% at 90 days Ptx in the treatment groups, indicating that 2-CdA has a prolonged, depletive effect on certain lymphocyte populations. DISCUSSION Heterotopic heart transplants were performed using LEW rats (RTl’ as the donor strain and F344 rats (RTl”) as the recipients. ) Heart grafts were harvested at the end of a 90-day period posttransplantation (PTx). Heart samples were subjected to histological examination and vascular lesions were analyzed with a computerized digital image system. RESULTS Our preliminary results demonstrate that 2-CdA in combination with CsA inhibits the development of transplant arteriosclerosis in rat cardiac allografts. 2-CdA is a recently developed anticancer compound that also has immunosuppressive properties when used for the treatment of multiple sclerosis.2a3 Its effect on the immune system includes lymphocyte depletion of both T- and B-cell populations. 2-CdA inhibits the proliferative changes associated with the development of TA and suggests that this effect is primarily due to the drug’ unique mechanism of immunosuppression. s REFERENCES Our results indicate that a reduction in the incidence and severity of the vascular intimal proliferative (VIP) lesions was associated with the treatment using 2-CdA in combination with CsA when compared with controls receiving no treatment or treatment with CsA alone (Table 1). A reduction in the intimal thickening was 69.8% (P = .005) when compared with no treatment and 48.2% (P = .05) compared with the CsA monotherapy group. Examination of peripheral blood samples suggested that T-cell counts, especially CD4+ T-helperiinTable 1. Histological 1. Cramer, DV: In Medical intelligence Unit, R.G. Landes Company: Graft Arteriosclerosis in Heart Transplantation. Austin/ Georgetown, 1993 2. Beutler E: Lancet 340:952, 1992 3. Oberhuber G, Schmid T, Thaler W, et al: Transplantation 581743, 1994 From the Transplantation Biology Research Laboratory, National Institute of Transplantation, St Vincent Medical Center (D.V.C., G-D.W., F.A.C.), Los Angeles, California, Department of Pathology, University of Southern California School of Medicine (C.M.), Los Angeles, California, and the Department of Molecular and Experimental Medicine, The Scripps Research Institute (D.R.S.), La Jolla, California, USA. of LEW Cardiac Allografts Findings for 2-CdA Treated FM4 Recipients HistologicalScore’(Mean ? SD) VIP Group 1 N L3 S L PVF S MI MF 1.18 ? 0.37 0.55 k 0.27 0.83 ? 0.32 2.69 1.74 t 0.38 0.44 2 0.24 0.66 i- 0.39 0.39 + 0.36 NA 0.88 k 0.71 0.47 +- 0.27 0.61 ? 0.27 2.00 1.25 ? 0.71 0.28 2 0.16 0.16 k 0.1 0.28 ? 0.2 NA 1.17 5 0.29 1.40 + 0.22 1 .oo + 0.5 2.00 1.30 * 0.41 0.42 c 0.14 0.70 _f 0.22 0.83 + 0.29 2.16 1.35 -t 0.68 ‘ VIP: Vascular intimal proliferation;PVF: perivascularfibrosis; Ml: myocardiuminflammation;MF: myocardiumfibrosis. ‘ Group 1: P-CdA 0.1 mg/kg. CsA 2.5 mg/kg; Group 2: P-CdA 0.1 mg/kg, CsA 5 mg/kg; Group 3: P-CdA 1 mgikg, CsA 5 mg/kg; Group 4: historic control (nontreatment). *L: Large vessels; S: Small intramyocardial vessels. 0041-1315/97/$17.00 PII SO041 -1345(96)00326 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 29, 616 (1997) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Transplantation Proceedings Elsevier

2-Chlorodeoxyadenosine in combination with cyclosporine inhibits the development of transplant arteriosclerosis in rat cardiac allografts

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Publisher
Elsevier
Copyright
Copyright © 1997 Elsevier Ltd
ISSN
0041-1345
D.O.I.
10.1016/S0041-1345(97)82533-X
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Abstract

ELSEVIER 2Ghlorodeoxyadenosine in Combination With Cyclosporine Inhibits the Development of Transplant Arteriosclerosis in Rat Cardiac Allografts D.V. Cramer, G.D. Wu, F.A. Chapman, C. Marboe, and DR. Salomon ONG-TERM SURVIVAL following organ transplantation has been associated with a high frequency of vascular disease (transplant arteriosclerosis, TA) in the muscular arteries of the donor graft. It is estimated that approximately 50% of heart graft recipients have evidence of coronary vascular disease 5 years following transplantation.’ The prevention of TA may depend on the development of more effective immunosuppression to prevent or treat chronic rejection without increasing the risk of adverse side effects. We have recently used a rat cardiac allograft model to evaluate an antitumor agent, 2-chlorodeoxyadenosine (2-CdA) in the prevention of TA. METHODS ducer cells, were reduced by 60% at 14 and 70% at 90 days Ptx in the treatment groups, indicating that 2-CdA has a prolonged, depletive effect on certain lymphocyte populations. DISCUSSION Heterotopic heart transplants were performed using LEW rats (RTl’ as the donor strain and F344 rats (RTl”) as the recipients. ) Heart grafts were harvested at the end of a 90-day period posttransplantation (PTx). Heart samples were subjected to histological examination and vascular lesions were analyzed with a computerized digital image system. RESULTS Our preliminary results demonstrate that 2-CdA in combination with CsA inhibits the development of transplant arteriosclerosis in rat cardiac allografts. 2-CdA is a recently developed anticancer compound that also has immunosuppressive properties when used for the treatment of multiple sclerosis.2a3 Its effect on the immune system includes lymphocyte depletion of both T- and B-cell populations. 2-CdA inhibits the proliferative changes associated with the development of TA and suggests that this effect is primarily due to the drug’ unique mechanism of immunosuppression. s REFERENCES Our results indicate that a reduction in the incidence and severity of the vascular intimal proliferative (VIP) lesions was associated with the treatment using 2-CdA in combination with CsA when compared with controls receiving no treatment or treatment with CsA alone (Table 1). A reduction in the intimal thickening was 69.8% (P = .005) when compared with no treatment and 48.2% (P = .05) compared with the CsA monotherapy group. Examination of peripheral blood samples suggested that T-cell counts, especially CD4+ T-helperiinTable 1. Histological 1. Cramer, DV: In Medical intelligence Unit, R.G. Landes Company: Graft Arteriosclerosis in Heart Transplantation. Austin/ Georgetown, 1993 2. Beutler E: Lancet 340:952, 1992 3. Oberhuber G, Schmid T, Thaler W, et al: Transplantation 581743, 1994 From the Transplantation Biology Research Laboratory, National Institute of Transplantation, St Vincent Medical Center (D.V.C., G-D.W., F.A.C.), Los Angeles, California, Department of Pathology, University of Southern California School of Medicine (C.M.), Los Angeles, California, and the Department of Molecular and Experimental Medicine, The Scripps Research Institute (D.R.S.), La Jolla, California, USA. of LEW Cardiac Allografts Findings for 2-CdA Treated FM4 Recipients HistologicalScore’(Mean ? SD) VIP Group 1 N L3 S L PVF S MI MF 1.18 ? 0.37 0.55 k 0.27 0.83 ? 0.32 2.69 1.74 t 0.38 0.44 2 0.24 0.66 i- 0.39 0.39 + 0.36 NA 0.88 k 0.71 0.47 +- 0.27 0.61 ? 0.27 2.00 1.25 ? 0.71 0.28 2 0.16 0.16 k 0.1 0.28 ? 0.2 NA 1.17 5 0.29 1.40 + 0.22 1 .oo + 0.5 2.00 1.30 * 0.41 0.42 c 0.14 0.70 _f 0.22 0.83 + 0.29 2.16 1.35 -t 0.68 ‘ VIP: Vascular intimal proliferation;PVF: perivascularfibrosis; Ml: myocardiuminflammation;MF: myocardiumfibrosis. ‘ Group 1: P-CdA 0.1 mg/kg. CsA 2.5 mg/kg; Group 2: P-CdA 0.1 mg/kg, CsA 5 mg/kg; Group 3: P-CdA 1 mgikg, CsA 5 mg/kg; Group 4: historic control (nontreatment). *L: Large vessels; S: Small intramyocardial vessels. 0041-1315/97/$17.00 PII SO041 -1345(96)00326 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 29, 616 (1997)

Journal

Transplantation ProceedingsElsevier

Published: Feb 1, 1997

References

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