Administration of a Negative Vaccination Induces Hyporesponsiveness to Islet Allografts

Abstract

As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund’s Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant.

Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes

“…scid , C57BL/6, or BALB/c pancreata as described [76–78]. Islet cells were 90% viable as determined by trypan blue (Gibco) exclusion assay.…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…In general, the microenvironment of the tolerant allograft can reveal a decrease in pro-inflammatory mediators (IFN-γ, TNF-α) and an increase in the anti-inflammatory mediator IL-10, as well as increased expression of the master regulator of Tregs, FoxP3 [157]. However, the IL-10 increase can be evidenced even during transplant rejection and ischemia in association with a wide range of inflammatory cells and cytokines [158].…”

“…Under resting conditions or at the initial time of response, the relatively low IL-10 production originates mainly from the cells of central immune system [159][160][161]. During the successive period, there is transient IL-10 induction, directly from the Bintact^immune system or under the manipulative effect of infective agents and tumor tissue [72,89,116,120,132,157,161]. Under such circumstances, the induced IL-10 functions at the crossroads of immune stimulation, whereas the outcome of this stimulation is mainly depended on the role of additional immune effectors [141].…”