Unexpected Immunoresponse to Gal and APA Antigens in Diabetic Type 1 Patients Receiving Neonatal Pig Islets After 6 Years

Abstract

Cotransplantation of porcine islets and Sertoli cells into preimplanted subcutaneous devices improve metabolic control in type 1 diabetic patients, and survive grafted for more than 4 years. We report here, further assessment of the endocrine and porcine nature of the surviving cells and the immune responses elicited toward Gal alpha(1,3)-Gal beta(1,4)-GlcNAc (Gal) antigen in patients who received a second and third transplants. No immunosuppressive drugs were administered. We were able to immunostain insulin- and glucagon-positive cells in all biopsies of patients and Sertoli cell markers in 60.9% of biopsies. Additionally, all biopsies tested, amplified the porcine COII gene. Patients demonstrated an increase in antipig antibodies in response to the first transplant with a decreasing response toward the second and third transplants. In all transplants, the IgG levels promptly returned to basal values after 3-4 months. The long-term survival of porcine cells and the reduced humoral immune response to multiple transplants indicate a form of tolerance. We have not been able to find CD25-positive cells, indicating that it is probably an immune accommodation of the graft.

Long-term follow-up of patients with type 1 diabetes transplanted with neonatal pig islets

“…All xenotransplanted patients showed insulin‐ and glucagon‐positive cells in biopsies from their grafts and some of the patients tested showed circulating porcine insulin after intravenous glucose tolerance test (IVGTT) regardless of the level of decrease in exogenous insulin requirements [18]. Anti‐pig antibodies (APA) and anti‐Gal antibodies were analysed [20] and porcine endogenous retrovirus (PERV) tests were negative [21]…”

Correlation between insulin requirements and anti-galactose antibodies in patients with type 1 diabetes transplanted with neonatal pig islets

“…They were screened during the clinical follow‐up for the presence of xenoantibodies at intervals from 2 to 8 weeks, in 2001, 2004 and 2007. We have already published the first xenoantibody levels 6 years post‐transplantation [19], but comparing only two groups depending on the cell culture type. In order to establish the immune competence of each patient, purified protein derivative (PPD) and haemocyanin tests, along with a C3c kinetic dosage, were performed.…”

Tissue transplantation by stealth—Coherent alginate microcapsules for immunoisolation

“…Similarly, co-encapsulation with immunomodulatory cells (e.g., Sertoli cells [23,32,[133][134][135][136]), or cells engineered to produce immunosuppressive drugs may be effective. This approach may be of particular interest in delivering ongoing protection for long durations (without depletion), or for induction of immune-tolerance or accommodation [23,137].…”