Transgenic Expression of CD95 Ligand on Thyroid Follicular Cells Confers Immune Privilege upon Thyroid Allografts

Abstract

Constitutive Fas ligand (FasL) expression by specialized cells in the body participates in the immune privilege status of tissues containing these cells. This property has been used to prevent rejection of allogeneic grafts. Nevertheless, the mechanism responsible for such protection has not been fully elucidated. Unfortunately, grafting of FasL transgenic (TG) tissues has been unsuccessful. We have generated TG mice expressing FasL (soluble + membrane bound) on thyroid follicular cells (TFC), and used them to show that ectopic FasL expression prevents thyroid allograft rejection. FasL expression on TFC led to markedly decreased anti-allogeneic, cytotoxic, and helper T lymphocyte activities. The alloantibody response in TG thyroid recipients was either completely inhibited or switched toward a T2-Ab response. Surprisingly, the beneficial effect of FasL on TG thyroid grafts was abolished by host CD4(+) T cell depletion. Host CD8(+) T cell depletion improved nontransgenic (NTG), but not TG graft survival. Altogether, our results suggest that FasL-induced tolerance is concomitant with a move away from a T1 type response, and a CD4 T cell-mediated regulation of the allocytotoxic T cell response. These results were dependent upon the level of FasL expression on TFC, in that low expression of FasL led to a less marked effect compared with the effect observed with high expression of FasL. These results provide some insight into the role of FasL in regulating destructive alloimmune responses in the case of whole organ grafting, and they have important implications for the development of FasL-based immunotherapy in organ transplantation.

Induction of tolerance using Fas ligand: a double-edged immunomodulator

“…68,69 This notion is consistent with the observation that CD4 ϩ T cells are important to FasLmediated immunoregulation since the depletion of these cells abolishes the protection conferred by FasL. 56 Particularly, naturally occurring CD4 ϩ CD25 ϩ Tregs were recently found to be resistant to apoptosis, possibly owing to their expression of high levels of antiapoptotic genes. 70 In transplantation settings, immunomodulation may not only prevent rejection, but also lead to central tolerance due to thymic selection of newly emerging T cells 71,72 continuously exposed to circulating donor antigens.…”

“…54 These initial observations were followed by a series of studies using FasL as an immunomodulatory agent with variable results. While some studies reported extended survival of allogeneic grafts, such as liver, kidney, thyroid, pancreatic islets, lung, and cornea, 55,56 others noted accelerated rejection of syngeneic and allogeneic grafts. [57][58][59] A common denominator in the latter studies was the presence of massive inflammatory infiltrates, particularly neutrophils, in FasL-expressing tissues and organs, suggesting that rejection was initiated by a delayed-type hypersensitivity reaction.…”

“…76 The use of FasL as an immunomodulatory agent to induce peripheral tolerance invokes several considerations. The level of expression of FasL appears to be important to its therapeutic potential, 56 and as such needs to be fine-tuned depending on the model system used and the tissue targeted for expression. High levels of FasL may have adverse effects on graft survival, 77 particularly if the graft lacks mechanisms required for proper regulation of this molecule.…”

Renal Tubular Epithelial Cell Self-Injury Through Fas/Fas Ligand Interaction Promotes Renal Allograft Injury

“…the eye and testes) by binding Fas on infiltrating leukocytes (15)(16)(17)(18)(19). However attempts to exploit this latter function for allograft protection have been complicated by different roles for soluble and membrane-bound FasL and the ability of cells to resist injury (20). Transgenic expression of FasL on islet cells induces greater cytotoxicity of neutrophils (21) while transgenic FasL expression in endogenous Fas-bearing cells may lead to a form of self injury (22,23).…”

Fas ligand mediates immune privilege and not inflammation in human colon cancer, irrespective of TGF-β expression

“…However, rodent transplantation experiments involving FasL have yielded conflicting results. Several groups demonstrated enhanced allograft survival following direct transfection of FasL cDNA into allografts (Li et al, 1998;Tourneur et al, 2001). Cotransplantation of FasL-negative allografts with FasL-expressing cells was also reported to prevent allograft rejection (Korbutt et al, 1997;Takeda et al, 1998).…”