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Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non-myeloablative regimen and CD154 blockade.

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Bühler, L Deng, S O'Neil, J Kitamura, H Koulmanda, M Baldi, A [UCL] Rahier, Jacques [UCL] Squifflet, Jean-Paul [UCL] Morel, Ph

The aim of the present study was to assess the survival of adult porcine islets transplanted into baboons receiving either (I) conventional triple drug immunosuppressive therapy or (2) a non-myeloablative regimen and an anti-CD154 monoclonal antibody (mAb) aimed at tolerance-induction. Group 1 baboons (n = 3) were pancreatectomized prior to intraportal injection of 10,000 porcine islet equivalents (IE)/kg and immunosuppressed with anti-thymocyte globulin (ATG), cyclosporine and azathioprine. In Group 2 (n = 2), non-pancreatectomized baboons underwent induction therapy with whole body and thymic irradiation, and ATG. Extracorporeal immunoadsorption (EIA) of anti-Galalpha1,3Gal (Gal) antibody was carried out. Maintenance therapy was with cobra venom factor, cyclosporine. mycophenolate mofetil, methylprednisolone and anti-CD154 mAb. Porcine islets were injected intraportally (14,000 and 32,000 IE/kg, respectively) and high-dose pig mobilized peripheral blood progenitor cells (3 x 10(10) cells/kg) were infused into a systemic vein. Porcine islets were also implanted in the sternomastoid muscle to facilitate subsequent biopsies. In both groups. porcine C-peptide was measured, and histological examination of liver or sternomastoid muscle biopsies was performed at regular intervals. In Group 1, total pancreatectomy reduccd human C-peptide to < 0.1 ng/ml and induced insulin-requiring diabetes. The transplantation of porcine islets was followed by normalization of glycemia for 15-24 h. Porcine C-peptide was detected only transiently immediately after porcine islet injection (maximum 0.12 ng/ml). Histological examination of liver biopsies taken between days 2 and 19 did not reveal viable islets, but necrotic cell structures with mononuclear cell infiltrates were identified in portal venules. In Group 2, injection of porcine islets into non-pancreatectomized recipients induced a transient hypoglycemia (2-4 h) requiring concentrated intravenous dextrose administration. Porcine C-peptide was detectable for 5 and 3 days (maximum 2.8 and 1.0 ng/ml), respectively. Baboon #4 died on day 12 from small bowel intussusception. Liver and sternomastoid muscle biopsies showed well-preserved porcine islets, staining positive for insulin and glucacon, without signs of rejection. In baboon #5, viable islets were detected in the sternomastoid muscle biopsy on day 14, but not on day 28 or thereafter. A progressive mononuclear cell and macrophage infiltration was seen in the biopsies. In conclusion, conventional immunosuppression allowed survival of porcine islets in baboons for < 24 h. The non-myeloablative regimen prolonged survival of porcine islets for > 14 days. However, despite depletion of T cells, anti-Gal antibody and complement, and CD154-hlockade, porcine islets were rejected by day 28. These results suggest that powerful innate immune responses are involved in rejection of discordant xenogencic islets.

Document type Article de périodique (Journal article) – Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Access type Accès restreint
Publication date 2002
Journal information "Xenotransplantation" - Vol. 9, no. 1, p. 3-13 (2002)
Peer reviewed yes
Publisher Munksgaard International Publishers ((Denmark) Copenhagen)
issn 0908-665X
Publication status Publié
Affiliations UCL - MD/MNOP - Département de morphologie normale et pathologique
UCL - MD/CHIR - Département de chirurgie
UCL - (SLuc) Service d'anatomie pathologique
UCL - (SLuc) Service de chirurgie et transplantation abdominale
MESH Subject Animals ; Antibodies, Monoclonal - therapeutic use ; Antilymphocyte Serum - therapeutic use ; Azathioprine - therapeutic use ; Cyclosporine - therapeutic use ; Drug Therapy, Combination ; Graft Survival - drug effects ; Immunosuppression - methods ; Immunosuppressive Agents - therapeutic use ; Islets of Langerhans Transplantation - immunology - pathology ; Pancreatectomy ; Papio ; Splenectomy ; Swine ; Thymus Gland - radiation effects ; Transplantation, Heterologous - immunology - pathology
Keywords Anti-CD154 monoclonal antibody ; Diabetes ; Islets of Langerhans ; Pancreatectomy ; Pig-to-primate model ; Xenotransplantation
Links
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Bibliographic reference Bühler, L ; Deng, S ; O'Neil, J ; Kitamura, H ; Koulmanda, M ; et. al. Adult porcine islet transplantation in baboons treated with conventional immunosuppression or a non-myeloablative regimen and CD154 blockade.. In: Xenotransplantation, Vol. 9, no. 1, p. 3-13 (2002)
Permanent URL http://hdl.handle.net/2078.1/28350