title: Transgenic anti-CD4 monoclonal antibody secretion by mouse segmental pancreas allografts promotes long term survival.
abstract: To compare the effectiveness of transgenic and systemic monoclonal antibody therapy for pancreas transplantation, vascularised segmental pancreas allografts from wild-type or transgenic pancreatic tissue that secreted monoclonal anti-CD4 were placed in CBA recipients in which diabetes had been induced chemically by streptozotocin (STZ, non-autoimmune diabetes). In untreated CBA recipients, wild-type BALB/c or C57BL/6 bml pancreas transplants were rejected in a mean survival time (MST) of 27 and 30 days, respectively. BALB/c and C57BL/6 graft survival improved when recipients were given a short course of T cell depleting monoclonal anti-CD4 antibody, (GK 1.5, 2 mg total on days -1, 0, 1, 2 with grafting on day 0) with MST +/- S.D. of 71 +/- 29 and 44 +/- 36 days, respectively. Thus, transient depletion of CD4 was effective in delaying pancreas allograft rejection in these strain combinations. The use of C57BL/6 bml mice transgenic for a rat anti-CD4 antibody (GK5 mice) as pancreas donors provided allografts that secreted sufficient anti-CD4 antibody to cause CD4 T cell depletion in the recipients (CD4 cells decreased from 30 to < 5% of small lymphocytes). This degree of depletion was not sustained and the CD4 recovery inversely correlated with graft survival. Mice with > 20% CD4 cells in the splenic lymphocyte population 4 weeks post-transplant rejected their grafts (3 of 10 mice). However, in 7 of 10 mice CD4 cells remained low (< 15%) and allografts survived for > 80 days. The GK5 allografts survived significantly longer than those from non-transgenic bml controls (MST 83 +/- 32 days, compared with 30 days, P < 0.0005). This survival time was similar to that of BALB/c allografts in CBA recipients treated with a high dose of anti-CD4 antibody. Thus, transgenic secretion of anti-CD4 antibody by the pancreas allograft was very effective in prolonging its survival.
authors.affiliation: University of Melbourne, Department of Surgery, and the Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Parkville, Australia. p.mottram@medicine.unimelb.edu.au
authors.forename: P L
authors.initials: PL
authors.lastname: Mottram
authors.forename: L J
authors.initials: LJ
authors.lastname: Murray-Segal
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: Y
authors.initials: Y
authors.lastname: Zhan
authors.forename: J L
authors.initials: JL
authors.lastname: Brady
authors.forename: A M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000235:genetics; D000961:Antilymphocyte Serum / Q000096:biosynthesis / Q000235:genetics; D015704:CD4 Antigens / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016035:Pancreas Transplantation / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D015704:CD4 Antigens; D011994:Recombinant Proteins