title: CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates.
abstract: The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Thompson
authors.forename: K
authors.initials: K
authors.lastname: Cardona
authors.forename: M
authors.initials: M
authors.lastname: Russell
authors.forename: I R
authors.initials: IR
authors.lastname: Badell
authors.forename: V
authors.initials: V
authors.lastname: Shaffer
authors.forename: G
authors.initials: G
authors.lastname: Korbutt
authors.forename: G R
authors.initials: GR
authors.lastname: Rayat
authors.forename: J
authors.initials: J
authors.lastname: Cano
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.forename: E
authors.initials: E
authors.lastname: Strobert
authors.forename: R
authors.initials: R
authors.lastname: Rajotte
authors.forename: T
authors.initials: T
authors.lastname: Pearson
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000077552:Basiliximab; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D005260:Female; D006085:Graft Survival; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008253:Macaca mulatta; D008297:Male; D011323:Primates; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D000077552:Basiliximab; D020123:Sirolimus