Allogeneic β-islet cells correct diabetes and resist immune rejection

Abstract

Allogeneic MHC-incompatible organ or cell grafts are usually promptly rejected by immunocompetent hosts. Here we tested allogeneic ␤-islet cell graft acceptance by immune or naïve C57BL͞6 mice rendered diabetic with streptozotocin (STZ). Fully MHC-mismatched insulin-producing growth-regulated ␤-islet cells were transplanted under the kidney capsule or s.c. Although previously or simultaneously primed mice rejected grafts, STZ-treated diabetic mice accepted islet cell grafts, and hyperglycemia was corrected within 2-4 weeks in absence of conventional immunosuppression. Allogeneic grafts that controlled hyperglycemia expressed MHC antigens, were not rejected for >100 days, and resisted a challenge by allogeneic skin grafts or multiple injections of allogeneic cells. Importantly, the skin grafts were rejected in a primary fashion by the grafted and corrected host, indicating neither tolerization nor priming. Such strictly extralymphatic cell grafts that are immunologically largely ignored should be applicable clinically.

Destruction of conditional insulinoma cell lines in NOD mice: A role for autoimmunity

“…Firstly, STZ differentially affected βTC-tet cell rejection in a pure allogenic or autoimmune model. As described by others [3], a high dose of STZ had a long-term protective effect on βTC-tet cell rejection by allogenic C57BL/6 mice. When the same experiment was carried out using young (3-to 6-week-old) NOD mice, a similar protective effect of STZ was observed.…”

“…βTC-tet cells survive indefinitely in STZ treated C57BL/6 mice [3], whereas in young STZ-treated male NOD mice, the grafts are secondarily rejected at a median age of 11 weeks. Here again, the differential pattern in C57BL/6 compared with NOD mice suggests the involvement of autoimmunity.…”

“…We stained 5-µm-thick sections of paraffin embedded transplanted kidney with hematoxilin-eosin. Additionally, Bcl-2 immunohistochemical staining was carried out with mouse anti-human Bcl2 monoclonal antibody (Ancell, P. Cattan et al: Destruction of conditional insulinoma cell lines in NOD mice: A role for autoimmunity 505 [3]. The survival of βTC-tet cells in an autoimmune environment has not been evaluated.…”

“…** when non diabetic recipients were used, hypoglycaemia was used as a readout of transplant function and histology was used to confirm graft implantation firm the protective effect of STZ in that setting [3], βTC-tet cell lines were transplanted in untreated and in STZ-diabetic C57BL/6 mice. In untreated recipients, no βTC-tet line function (Bcl-2 in combination with MyD88lpr, n=5 or Bcl-2 in combination with SOCS-1, n=5) was observed and histological analysis of transplanted kidneys done 3 weeks after transplantation showed a complete disappearance of the graft.…”

“…When transplanted in syngenic or allogenic mice made diabetic with a high dose i.v. streptozotocin (STZ), these cells durably reverse hyperglycaemia in 2 to 4 weeks [2,3]. Administration of tetracyclin to recipient mice prevents the development of massive tumours and death from hypoglycaemia.…”