Testicular Sertoli cells exert both protective and destructive effects on syngeneic islet grafts in non-obese diabetic mice

Korbutt, Gregory S.; Suarez-Pinzon, Wilma L.; Power, Robert F.; Rajotte, Ray V.; Rabinovitch, Alex

doi:10.1007/s001250051331

Cited by 65 publications

(47 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Paraffin sections of formalin fixed samples were stained with hematoxylin and eosin, and for insulin staining using immunoperoxidase, as described (28).…”

Section: Immunohistopathologymentioning

confidence: 99%

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Truong

Plester

Hancock

et al. 2007

American Journal of Transplantation

View full text Add to dashboard Cite

Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.

show abstract

“…Paraffin sections of formalin fixed samples were stained with hematoxylin and eosin, and for insulin staining using immunoperoxidase, as described (28).…”

Section: Immunohistopathologymentioning

confidence: 99%

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Truong

Plester

Hancock

et al. 2007

American Journal of Transplantation

View full text Add to dashboard Cite

show abstract

“…18,19 Co-transplantation of testicular Sertoli cells also protected islet grafts from rejection in a similar manner to HSCs 19 ; however, the protective effect of HSCs appears to be more potent than that of Sertoli cells because the required cell number of HSCs (3 ϫ 10 5 ) was approximately one-tenth of Sertoli cells (4 ϫ 10 6 to 11 ϫ 10 6 ). 20,21 Differences are also manifest by local versus systemic effects. HSCs implanted distantly from islet allografts did not show protection.…”

Section: Discussionmentioning

confidence: 99%

In vivo immune modulatory activity of hepatic stellate cells in mice

et al. 2006

View full text Add to dashboard Cite

Accumulating data suggest that hepatic tolerance, initially demonstrated by spontaneous acceptance of liver allografts in many species, results from an immune regulatory activity occurring in the liver. However, the responsible cellular and molecular components have not been completely understood. We have recently described profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro. In this study, we demonstrate in vivo evidence of immune modulatory activity of HSCs in mice using an islet transplantation model. Cotransplanted HSCs effectively protected islet allografts from rejection, forming a multilayered capsule, which reduced allograft immunocyte infiltrates by enhancement of apoptotic death. The immune modulation by HSCs appeared to be a local effect, and regulated by inducible expression of B7-H1, an inhibitory molecule of B7 family. This may reflect an intrinsic mechanism of immune inhibition mediated by liver-derived tissue cells. H epatic tolerance was initially recognized by spontaneous acceptance of liver allografts in a number of species. 1-4 Our laboratory focused on the mechanistic insights into liver transplant tolerance in mice and demonstrated that it is not attributable to a deletion of T cell clones specific to donor antigens, because lymphocytes isolated from tolerant mice respond well to donor antigen stimulation in vitro. 5 Whereas histological findings are notable for an abundance of CD4 and CD8 T cell infiltrates during the first week after transplantation, they are rapidly diminished via apoptotic death. [6][7][8] Similarly, in a nontransplant model, after injection of a specific antigenic peptide into TCR transgenic mice, deletion of specific CD8 ϩ T cells from the periphery was observed, as they accumulated in the liver and underwent subsequent apoptosis. 9 Combined, these results suggest a regulatory mechanism residing in the liver that may be responsible for its immune modulation. 10 However, the cellular components of the liver responsible for this are not completely understood.We have recently demonstrated that activated hepatic stellate cells (HSCs) effectively inhibit T cell responses in vitro, which is mediated by induction of T cell apoptosis. 11 Thus, subsequently studying whether HSCs can exert immune regulatory activities in vivo is logical. However, it is difficult to obtain direct evidence in the liver because approaches to specifically inhibit the effect of HSCs have not been defined. In this study, we used an islet allograft transplant model and demonstrated that cotransplantation with HSCs effectively protected islet allografts from rejection by forming a multi-layered immune barrier around the islets and reducing infiltrating T cells. Interestingly, HSCs isolated from B7-H1 knockout (KO) mice lost the protective effect on co-transplanted islet

show abstract

“…74 This conclusion had been challenged by the observation that neutralizing antibodies to FasL did not reduce the survival of islets in diabetic mice after cotransplantation with SCs. 75 FasL is predominantly expressed in male germ cells, but not in SCs. 33 Whether FasL that is expressed in the germ cells induces lymphocyte apoptosis and contributes to immune privilege within the seminiferous tubules remains to be investigated.…”

Section: Immune Privilege In the Testismentioning

confidence: 96%

Testicular defense systems: immune privilege and innate immunity

et al. 2014

View full text Add to dashboard Cite

The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.

show abstract

Testicular Sertoli cells exert both protective and destructive effects on syngeneic islet grafts in non-obese diabetic mice

Cited by 65 publications

References 37 publications

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

In vivo immune modulatory activity of hepatic stellate cells in mice

Testicular defense systems: immune privilege and innate immunity

Contact Info

Product

Resources

About