The specificity of rejection and the absence of susceptibility of pancreatic islet beta cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat.

Abstract

The specificity of rejection of isolated pancreatic islets was examined in the rat using a quantitative model in which syngeneic (DA) or a mixture of syngeneic and allogeneic (DA and LEW or PVG) islets were implanted beneath the capsule of the kidney of nondiabetic normal rats (DA). 3 wk after transplantation total insulin extraction assays of the kidney with its islet implant together with immunohistological examination of the site of transplantation for evidence of syngeneic or allogeneic tissue demonstrated the total destruction of allogeneic islets without any evidence of damage to syngeneic islets either distant or in immediate proximity to allogeneic islets. Pancreatic islets, and especially beta cells, appear to be particularly vulnerable to the effector arm of both autoimmune and alloimmune responses, a vulnerability that has been attributed to the cytotoxic effects of lymphokines, notably IL-1, released in both autoimmune and alloimmune responses. The experiments reported here demonstrate not only the exquisite specificity of the allograft reaction but are not compatible with a hypothesis that B cells within an intact islet are nonspecifically susceptible to destruction by lymphokines.

Control of In Vivo Collateral Damage Generated by T Cell Immunity

“…Such bystander killing has been shown to be mediated by Fas/Fas ligand (CD95/CD95 ligand) interactions or by TNF (1) and was dependent on the allele of MHC expressed by the "bystander" cells in some settings (2) but not others (4). In transplant models, using a mixture of syngeneic and allogeneic or xenogeneic islets (5,6) or with allophenic skin grafts (7,8), results supported the concept of selective killing of specific target cells. In contrast, other skin transplant models have shown significant bystander damage to adjacent syngeneic cells (9), and bystander injury occurred in mixed xenogeneic and syngeneic islets in primed recipients (10).…”

The role of perforin and granzymes in diabetes

“…62 There is evidence that allogeneic rejection of islets is contact-dependent because grafts consisting of mixed syngeneic and allogeneic islets resulted in the destruction of only the allogeneic islets. 63 It remains unclear how allografts are destroyed in vivo, but clearly perforin-independent mechanisms exist.…”

Allophenic Mice: A Pillar Awaiting Its Superstructure

“…This pattern suggests that allospecific cytotoxic cells rather than nonspecific effector mechanisms, such as the action of cytokines, destroy allogeneic patches. Consistent with this concept, Sutton et al (15), studying grafts consisting of admixed allogeneic and syngeneic islets of Langerhans, observed that the allogeneic islets were destroyed whereas syngeneic islets, even those adjacent to allogeneic islets, survived. However, neither of these seminal studies provides a fully satisfying answer.…”