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.
CD40‐specific costimulation blockade can substitute for CD154‐specific therapies to protect neonatal porcine islet xenografts.
Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 ...pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154‐directed therapies. Prior CD40‐directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40 blockade‐based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40‐specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor‐specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long‐term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8‐based regimen. Thus, CTLA4Ig combines with a CD40‐specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor‐free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.
CTLA4Ig prevents donor‐specific antibody formation in nonhuman primates transplanted allogeneic islets using an immunosuppressive regimen consisting of the CD40‐specific antibody 3A8, basiliximab and sirolimus.
Recent advances in human allogeneic islet transplantation have established β‐cell replacement therapy as a potentially viable treatment option for individuals afflicted with Type 1 diabetes. Two ...recent successes, one involving neonatal porcine islet xenografts transplanted into diabetic rhesus macaques treated with a costimulation blockade‐based regimen and the other involving diabetic cynomolgus monkeys transplanted with adult porcine islet xenografts treated with an alternative multidrug immunosuppressive regimen have demonstrated the feasibility of porcine islet xenotransplantation in nonhuman primate models. In the current study, we assessed whether transplantation of adult porcine islet xenografts into pancreatectomized macaques, under the cover of a costimulation blockade‐based immunosuppressive regimen (CD28 and CD154 blockade), could correct hyperglycemia. Our findings suggest that the adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade‐based regimen are not uniformly subject to hyperacute rejection, can engraft (2/5 recipients), and have the potential to provide sustained normoglycemia. These results provide further evidence to suggest that porcine islet xenotransplantation may be an attainable strategy to alleviate the islet supply crisis that is one of the principal obstacles to large‐scale application of islet replacement therapy in the treatment of Type 1 diabetes.
Adult porcine islets transplanted into rhesus macaques receiving a costimulation blockade‐based immunosuppressive regimen (CD28/CD154 blockade plus basiliximab and sirolimus) are not uniformly subject to hyperacute rejection, can engraft, and have the potential to provide sustained normoglycemia.
A strategy for producing high‐level hematopoietic chimerism after non‐myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell ...transplantation after induction with a non‐myeloablative dose of busulfan and blockade of the IL2‐receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high‐level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre‐transplant CD8 depletion, donor‐specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor‐specific down‐regulation of alloreactive T cells, and the reappearance of vigorous T‐mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant‐related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism‐induction regimen induced amongst the longest‐lived stem cell chimerism reported to date for non‐human primates and thus represents a platform upon which to evaluate emerging tolerance‐induction strategies.
A strategy of stem cell transplantation plus busulphan, IL‐2 receptor blockade, sirolimus, and combined CD28/CD154 costimulation blockade induced donor cell chimerism for a median of 145 days, but viral reactivation constituted a significant toxicity.
We evaluated the ability of neonatal porcine islets to engraft and restore glucose control in pancreatectomized rhesus macaques. Although porcine islets transplanted into nonimmunosuppressed macaques ...were rapidly rejected by a process consistent with cellular rejection, recipients treated with a CD28-CD154 costimulation blockade regimen achieved sustained insulin independence (median survival, >140 days) without evidence of porcine endogenous retrovirus dissemination. Thus, neonatal porcine islets represent a promising solution to the crucial supply problem in clinical islet transplantation.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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