title: Combination of anti-CD4 with anti-LFA-1 and anti-CD154 monoclonal antibodies promotes long-term survival and function of neonatal porcine islet xenografts in spontaneously diabetic NOD mice.
abstract: Type 1 diabetes mellitus (T1DM) is caused by the autoimmune destruction of pancreatic islet beta-cells, which are required for the production of insulin. Islet transplantation has been shown to be an effective treatment option for TIDM; however, the current shortage of human islet donors limits the application of this treatment to patients with brittle T1DM. Xenotransplantation of pig islets is a potential solution to the shortage of human donor islets provided xenograft rejection is prevented. We demonstrated that a short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) was highly effective in preventing rejection of neonatal porcine islet (NPI) xenografts in non-autoimmune-prone B6 mice. However, the efficacy of this therapy in preventing rejection of NPI xenografts in autoimmune-prone nonobese diabetic (NOD) mice is not known. Given that the current application of islet transplantation is for the treatment of T1DM, we set out to determine whether a combination of anti-LFA-1 and anti-CD154 mAbs could promote long-term survival of NPI xenografts in NOD mice. Short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs, which we found highly effective in preventing rejection of NPI xenografts in B6 mice, failed to promote long-term survival of NPI xenografts in NOD mice. However, addition of anti-CD4 mAb to short-term treatment of a combination of anti-LFA-1 and anti-CD154 mAbs resulted in xenograft function in 9/12 animals and long-term graft (>100 days) survival in 2/12 mice. Immunohistochemical analysis of islet grafts from these mice identified numerous insulin-producing beta-cells. Moreover, the anti-porcine antibody as well as autoreactive antibody responses in these mice was reduced similar to those observed in naive nontransplanted mice. These data demonstrate that simultaneous targeting of LFA-1, CD154, and CD4 molecules can be effective in inducing long-term islet xenograft survival and function in autoimmune-prone NOD mice.
authors: Surgical-Medical Research Institute, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: Hossein
authors: H
authors: Arefanian
authors: Eric B
authors: EB
authors: Tredget
authors: Ray V
authors: RV
authors: Rajotte
authors: Gregory S
authors: GS
authors: Korbutt
authors: Ron G
authors: RG
authors: Gill
authors: Gina R
authors: GR
authors: Rayat
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D003131:Combined Modality Therapy; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000628:therapy; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D015704:CD4 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand