Achieving Permanent Survival of Islet Xenografts by Independent Manipulation of Direct and Indirect T-Cell Responses

Abstract

Recent success in pancreatic islet allotransplantation has raised expectations but has equally highlighted the acute shortage of donor tissue. The use of xenogeneic tissue would help to address this shortage; however, strong cellular immunity limits the application of this approach. T-cell responses to xenogeneic tissues involve recognition of intact species-mismatched major histocompatibility complex (MHC) molecules, the direct pathway, and xenogeneic proteins presented as peptides by responder-type MHC molecules, the indirect pathway. In this study, we exploited the species difference to selectively and sequentially inhibit direct and indirect xenoresponses after transplantation of porcine islets into mice. Selective inhibition of the direct response was achieved using porcine CTLA4-Ig, which binds preferentially to pig versus mouse B7 molecules. Selective inhibition of the indirect response was achieved using murine CTLA4-Ig, which binds preferentially to mouse B7 molecules. Administration of porcine CTLA4-Ig alone caused modest prolongation of islet survival. Injection of murine CTLA4-Ig alone had a minimal effect. However, the injection of the porcine fusion protein early and the murine homolog late after grafting led to permanent survival of the porcine islets, in the absence of any other immunosuppression. These results suggest that a similar approach could have clinical utility in porcine islet xenotransplantation.

Pancreatic-Derived Pathfinder Cells Enable Regeneration of Critically Damaged Adult Pancreatic Tissue and Completely Reverse Streptozotocin-Induced Diabetes

“…Our data are again, not inconsistent with these data. Fifth, our data are consistent with reports detailing bone marrow-derived c-kit-positive stem cells initiating endogenous pancreatic tissue regeneration in vivo 15,17 and with stimulation of endogenous neural repair using exogenous stem cells in mice. 18 However, the mechanism of the induced repair has not been elucidated in either instance.…”

“…All procedures were conducted under the authority of the UK Home Office (HO) and performed as described previously. 15 Under these licensing conditions, animals with blood glucose above 30 mM/L or a body weight loss of 20% or more were required to be sacrificed. In this protocol, diabetes is defined as serial nonfasting glucose levels, 3 days post-STZ and beyond, of >20 mM/L.…”

Growing organs for transplantation from embryonic precursor tissues

“…However, our study showed that upon transplantation into mouse strains with various immunological defects, rejection is primarily dependent on T cell responses [16]. Other studies describing xenorejection of later gestational age pig pancreas and adult pig islets also support this conclusion [35,36]. In this context, it is likely that immunosuppressive agents, such as co-stimulatory blocking agents, directed against T cell activation and with minimal impact on angiogenesis and/or embryonic growth and development, might be effective.…”

Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice

“…In general, the early embryonic stage might render the implanted donor tissue less immunogenic 44,45 ; however, we previously demonstrated that such transplants cannot evade the indirect rejection pathway 15,46,47 . Nevertheless, this challenge can be addressed by protocols including costimulatory blockade 48,49 . Alternatively, the substantial numbers of hematopoietic progenitors in the embryonic lung tissue (data not shown) might result in hematopoietic chimerism that could induce central tolerance toward donor-derived lung cells after transplantation 50 .…”