A novel multimeric form of FasL modulates the ability of diabetogenic T cells to mediate type 1 diabetes in an adoptive transfer model

Abstract

Activation induced cell death (AICD) via Fas/FasL is the primary homeostatic molecular mechanism employed by the immune system to control activated T-cell responses and promote tolerance to self-antigens. We herein investigated the ability of a novel multimeric form of FasL chimeric with streptavidin (SA-FasL) having potent apoptotic activity to induce apoptosis in diabetogenic T cells and modulate insulin-dependent type 1 diabetes (IDDM) in an adoptive transfer model. Diabetogenic splenocytes from NOD/Lt females were co-cultured in vitro with SA-FasL, SA control protein, or alone without protein, and adoptively transferred into NOD/Lt-Rag1(null) recipients for diabetes development. All animals receiving control (Alone: n=16 or SA: n=17) cells developed diabetes on average by 6 weeks, whereas animals receiving SA-FasL-treated (n=25) cells exhibited significantly delayed progression (p<.001) and decreased incidence (70%). This effect was associated with an increase in CD4(+)CD25(+) T cells and correlated with FoxP3 expression in pancreatic lymph nodes. Extracorporeal treatment of peripheral blood lymphocytes using SA-FasL during disease onset represents a novel approach that may alter the ability of pathogenic T cells to mediate diabetes and have therapeutic utility in clinical management of IDDM.

Killer Treg restore immune homeostasis and suppress autoimmune diabetes in prediabetic NOD mice

“…In contrast, overexpression of FasL protein on the surface of adoptively transferred CD25 þ T cells reduced the incidence of diabetes to 20% (2/10), demonstrating that FasL augments the suppressive function of CD25 þ cells in vivo. Reduced pathogenic activity is consistent with partial protection from disease transfer by preincubation of NOD splenocytes with FasL ex vivo [32] and extend these findings by demonstration of sustained veto activity of FasL in vivo.…”

“…Fourth, FasL can be employed for immunomodulation in conjunction with other strategies aiming to sensitize, expand and enhance the suppressive activity of Treg to arrest autoimmunity [16,26e28]. FasL is a physiological constituent of apoptotic signals transduced by human and murine adaptive Treg cells [13] and has the significant advantage of selective and antigen-specific elimination of autoreactive and alloreactive effector cells [18,19,23,32,53]. Finally, the most prominent feature of CD25 þ -FasL immunomodulation is to create a substantial disease-free window of opportunity during which additional approaches to definitive arrest of autoimmunity might be implemented prior to institution of therapies to replenish the damaged tissue [54].…”

Immunomodulation With SA-FasL Protein as an Effective Means of Preventing Islet Allograft Rejection in Chemically Diabetic NOD Mice

“…This prediction is consistent with our previous observations that SA-FasL protein preferentially induces apoptosis in autoreactive T-effector cells in NOD while sparing CD4 + CD25 + FoxP3 + T-regulatory (Treg) cells. 11 Although we do not know the mechanistic basis of long-term allogeneic islet survival in the present study, it is tempting to speculate that active immune regulation, plausibly by Treg cells, may play a role. This notion is consistent with our recent studies demonstrating that SA-FasL–engineered allogeneic islets achieve localized tolerance by inducing Treg cells.…”

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…2b), demonstrating effective depletion of pathogenic cells. Similar depletion of diabetogenic cells has been achieved by pre-incubation with Fas ligand before adoptive transfer into immunocompromised mice [26]. Impact of cyclophosphamide and IL2-cas on diabetes in NOD mice In view of the evidence that IL2-cas induces apoptosis in CD25 + T cells and decreases effector activity, the fusion protein was evaluated in NOD mice in vivo.…”