Cytokine Gene Expression in Pancreatic Islet Grafts in the Rat1

Abstract

We examined the production of cytokine message in allogeneic and syngeneic rat pancreatic islet grafts using specific primers and polymerase chain reaction. Freshly isolated islet preparations contained transcripts for interleukin (IL)-1alpha, IL-6, IL-10, and interferon-gamma (IFN-gamma) but not for IL-2. IL-1alpha in allogeneic grafts showed increased and consistently high expression from 1 to 7 days after transplantation, but the level in syngeneic grafts fell quickly to pretransplant levels. IL-2 and IFN-gamma transcripts were found in allogeneic grafts at 1, 3, 5, and 7 days after transplantation with a peak at day 5, but these cytokines were almost absent from syngeneic grafts. The peak of IL-6 expression was 1 day after transplantation in both syngeneic and allogeneic grafts, and then the level fell quickly. IL-10 was produced at approximately the same high level at all time points in both syngeneic and allogeneic grafts. The results show that freshly isolated islet preparations contain IL-1alpha, IL-6, IL-10, and IFN-gamma transcripts at the time of transplantation. The initial production of cytokines in islet grafts, especially IL-1, may explain phenomena such as graft nonfunction, rapid rejection, and lack of response to immunosuppression.

Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome

“…In addition, non-specific inflammation at the grafted site, involving the expression of pro-inflammatory cytokines, is considered to play a role in early graft failure [4,5,12,13]. We have identified increased production of IL-1β in syngeneically transplanted islet grafts, thereby confirming the presence of an inflammatory process in early islet transplantation even in most favourable conditions for islet survival [14,15].…”

Anti-LFA-1 Therapy Induces Long-Term Islet Allograft Acceptance in the Absence of IFN-γ or IL-4

“…Unmodified graft rejection is usually associated with Th1-like cytokines (23,24,33), although Th2 cytokines (e.g., IL-4 and IL-10) can also be elevated in rejecting grafts (32,33). In contrast, allograft tolerance is often characterized by decreased expression of IL-2 and IFN-␥ and/or elevated Th2 cytokines (26 -31).…”

“…Acutely rejecting tissues are typically characterized by elevated proinflammatory Th1-like cytokines (23)(24)(25), while transplantation tolerance has often been associated with reduced Th1 cytokines or the emergence of Th2 cytokines (26 -31). Although Th1 and Th2 cells have been postulated to explain allograft rejection and tolerance, respectively, this simple paradigm has been called into question (25).…”

DcR3/TR6 Effectively Prevents Islet Primary Nonfunction After Transplantation

“…What is the physiologic relevance of IFN-␥ in PNF, which is defined as a reaction unrelated to classical allograft rejection? Although a definitive cell source of IFN-␥ production during PNF remains to be elucidated, IFN-␥ mRNA can indeed be detected in freshly isolated islets (22). Also, it is known that memory T-cells under the influence of inflammatory cytokines can nonspecifically produce IFN-␥ without Tcell receptor ligation (23).…”