Sertoli Cell-Enriched Fractions in Successful Islet Cell Transplantation

Abstract

Prolonged survival of Islet- allo- and xenografts can be induced following implantation of the islets into the abdominal testis of diabetic rats. We previously showed that a factor released by Sertoli cells appears to be responsible for the protection of the intratesticular islet allo- and xenografts against rejection. The aim of this study was to examine whether an immunologically privileged site can be established in an organ site in vivo, other than the testis, such as the renal, subcapsular space, to make feasible the grafting of female recipients as well. A total of 36 male and 21 female, diabetic, PVG rats were divided into six different treatment groups: 1) Six male rats were grafted with islets from Sprague-Dawley (S-D) donor rats only. 2) Ten male rats were grafted with islets from (S-D) donors and were then given a short course of cyclosporine (CsA) posttransplantation. 3) Ten male rats were grafted with islets from (S-D) donors and with Sertoli cell-enriched fractions (SEF) from PVG donors but without CsA. 4) Ten male rats were grafted with a combination of islets from (S-D) and SEF from (PVG), donors, respectively, and CsA. 5) Ten female rats were given an identical combination of cells and CsA as depicted for group 5. 6) Ten female rats were grafted with a combination of islets and SEF, both cell types from S-D donors, and CsA. The results showed that 70% to 100% of the grafted rats in groups 1, 2, and 3 remained hyperglycemic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice

“…These two biological factors must have increased accessibility of injected virus particles to Sertoli cells in the seminiferous tubules and may have allowed us to use low virus titers (1 to 20 ϫ 10 5 pfu͞ml) in inducing Sertoli cell infection without triggering inflammation, as observed in the previous study using significantly higher virus titer (3 ϫ 10 12 pfu͞ml) (18). Although much remains to be investigated about the level of immune privilege in the testis, studies have shown that even dissociated Sertoli cells have ability to suppress rejection after transplantation (33,34), and this local immunosuppresion by Sertoli cells must have contributed to the absence of inflammatory reaction. Other factors also may be involved, but the unique microenvironment in the infertile testis may account for the long-term transgene expression in Sertoli cells seen in this study.…”

Genetically engineered Sertoli cells are able to survive allogeneic transplantation

“…[1][2][3][4] This immunoprotective environment is due in part to the secretion of immunosuppressive molecules by Sertoli cells (SCs) [5][6][7] that allow ectopically transplanted SCs to survive as allografts [8][9][10] and concordant (rat-to-mouse) 11 and discordant (pig-to-rat) 12,13 xenografts in rodents. In addition to the ability of transplanted SCs to protect themselves in immunologically foreign environments, SCs were shown to protect islets and neuronal cells from immunemediated rejection.…”

“…In addition to the ability of transplanted SCs to protect themselves in immunologically foreign environments, SCs were shown to protect islets and neuronal cells from immunemediated rejection. 9,10,[14][15][16][17][18][19] The ability of SCs to protect themselves from immunemediated destruction, as well as their ability to produce a variety of proteins, has novel and potentially far-reaching implications for gene therapy. Gene therapy is an emerging field with the goal of replacing defective and deficient proteins to restore function in disease states.…”

“…While the use of SCs to deliver therapeutic proteins has potential applications across numerous clinical situations, the greatest amount of data collected to date have been focused on diabetes and Parkinson's disease (PD). 9,10,[14][15][16][17][18][19] It is not our goal to review these data here; however, it seems intuitively obvious that the consistent ability to graft SCs in animal models of diabetes and PD successfully provides a strong foundation for further exploration of transgenic SCs in these same preclinical systems. For instance, islet transplantation for the treatment of type I diabetes was recently demonstrated to be a viable option.…”

Apoptosis signaling by death receptors

“…Recently, in humans a similar disease with a dysfunction of CD95 was reported [43Ϫ45]. Children with autoimmune lym-layed rejection when co-implanted with CD95L-expressing testis tissue [63]. phoproliferative syndrome (ALPS), also called Canale-Smith syndrome, have massive nonmalignant lymphadenopathy, hepa-CD95L-mediated depletion of cytotoxic T-lymphocytes may not only be beneficial but may also play a role for tumor cells tosplenomegaly, altered T cell populations and other manifestations of systemic autoimmunity.…”