Transplantation of organ‐cultured fetal pancreas: Experimental studies and potential clinical application in diabetes mellitus

Abstract

Transplantation of organ-cultured fetal islets of Langerhans may be one way of overcoming the dual difficulties of finding a suitable source of tissue and controlling graft rejection. Experiments in mice have clearly shown that fetal pancreas is an excellent source of islets. Tissue from one donor can be used to treat one or more recipients and provides excellent control of drug-induced diabetes, including prevention of diabetic renal microangiopathy. The fetal islets display selective survival in vitro and organ culture can be used to obtain large amounts of tissue for transplantation. In addition, growth in "normoglycemic" media results in functional maturation of the fetal tissue.Culture conditions can be modified to eliminate from the putative graft immunogenic "passenger leukocytes," the cells responsible for initiating graft rejection. Such immunogenic cell-depleted grafts can be transplanted across histocompatibility barriers without the need for recipient immunosuppression.Fetal human pancreas shares n~any properties in common with fetal mouse pancreas. Continuing growth and differentiation occur in vitro and following xenotransplantation into athymic mice. However, fetal human pancreas is frequently damaged by ischemia before it can be used, and also appears to be more susceptible to oxygen toxicity than is fetal mouse pancreas. Nevertheless, when fresh human tissue is available, it may be a suitable source of islets for transplantation in type I diabetics.

A Comparison of Portal Versus Systemic Venous Drainage in Murine Foetal Pancreatic Islet Transplantation

“…We generally placed the grafts under the renal capsule where islets derived from less than one half of a foetal pancreas produced euglycaemia in each recipient (Mandel, 1984). However, these grafts drained insulin into the systemic venous circulation and therefore the physiological first-pass of the hormone through the liver was absent (Madison et al, 1958;Blackard and Nelson, 1971;Felig, 1975).…”

“…Studies from this laboratory have clearly shown that it is possible to reverse streptozotocin-induced diabetes in mice with either isografts (Mandel, 1984) or allografts (Collier and Mandel, 1983;Georgiou and Mandel, 1984;Georgiou and Mandel, 1985a and b) of organ-cultured foetal pancreas. We generally placed the grafts under the renal capsule where islets derived from less than one half of a foetal pancreas produced euglycaemia in each recipient (Mandel, 1984). However, these grafts drained insulin into the systemic venous circulation and therefore the physiological first-pass of the hormone through the liver was absent (Madison et al, 1958;Blackard and Nelson, 1971;Felig, 1975).…”

Effects of streptozotocin on autoimmune diabetes in NOD mice

“…However, numerous studies of both islet allotransplantation and xeno‐transplantation after streptozotocin treatment have shown rapid rejection of these grafts [3,5,27,36,37,43,44]. Thus, it is unlikely that streptozotocin prevented the onset of autoimmunity and reversed it in our studies simply on the basis of its mild immunosuppressive properties.…”