Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Abstract

Allogeneic mouse islets or xenogeneic rat islets, or fetal porcine islets were implanted under the renal capsule ofC57BL/6 mice either alone or carefully mixed with syngeneic islets. With this experimental model the syngeneic islets, although not rejected themselves, are exposed to cytokines and inflammatory mediators released during either allograft or xenograft rejection. No differences in insulin content could be observed between mixed islet grafts and pure syngeneic islet grafts 6 wk after transplantation. Neither was there any morphological evidence of a nonspecific destruction of syngeneic islets. These findings suggest that the mechanisms of both allograft and xenograft rejections are highly specific. The hormone release from the mixed syngeneic-allogeneic grafts was similar to that from pure syngeneic islet grafts. In contrast, a pronounced impairment of both the first and second phases of insulin release was observed 2 wk after implantation in mixed syngeneic-xenogeneic islet grafts. When perfusing the mixed islet graft after completed rejection of the concordant xenogeneic rat islets (6 wk after implantation), the insulin release from the remaining syngeneic mouse islets was identical to that of control grafts. However, syngeneic mouse islets exposed to the rejection mechanism of the discordant xenogenic pig islet-like cell clusters did not attain a complete functional recovery. (J. Clin. Invest. 1994. 93:1113-1119

Xenograft rejection of fetal porcine islet‐like cell clusters in the rat: effects of active and passive immunization

“…In rats, most of the infiltrating macrophages express the CD4 antigen and, with time, also the CD8 antigen and the macrophage‐specific differentiation antigen ED2. Even though the macrophage is the main infiltrating cell type, the specificity of xenograft rejection (no bystander killing) appears to be similar to that seen in allograft rejection, as previously demonstrated in a mixed islet‐graft model [3]. Xenograft rejection proceeds mainly unaffected in mice deficient in natural killer (NK) cells [4], or in mice with targeted disruption of the FcR γ‐chain or the membrane exon of the immunoglobulin µ‐chain gene [5].…”

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).…”

Genetic Engineering of a Suboptimal Islet Graft with A20 Preserves β Cell Mass and Function

“…We aimed to determine the in vivo cytoprotective effect of A20 in islets, by addressing whether A20 would enhance the survival and function of a suboptimal islet mass transplanted into syngeneic diabetic mice (30,31). We defined the suboptimal islet mass as the number of transplanted islets that would have a Ͻ25% success rate in restoring euglycemia within 2-5 days.…”

“…A significantly higher number (p Ͻ 0.0005) of insulin-positive cells per region was detected in rAd.A20-infected islets compared with rAd.␤-gal-infected islets (M). To determine whether A20 would protect islets in vivo, we studied a transplant model using a suboptimal islet mass (30,31). We determined the number of islets that would result in a Ͻ25% cure rate when transplanted into diabetic recipients.…”