The detrimental immune response of auto-reactive and allo-reactive T cells to host antigens is the fundamental and therapeutic problem in autoimmunity and transplantation, respectively. For example, to impart an effective cure for type 1 diabetes (T1D), we would need to:
- Prevent or halt the T cell-mediated destruction of insulin-producing, pancreatic beta cells.
- Preserve the host islet cell mass or its surgically-supplied replacement islets from destruction by antigen-specific T cells.
To date, these goals remain unfulfilled.
While progress has been made with new non-steroidal T cell immunosuppressive drugs, we must still resort to global suppression of T cell-mediated immunity to inhibit the few deleterious effector T cells responsible for syngeneic or allogeneic islet cell destruction.
Recently, we found that as T cells transition between their three major states – naïve, activated and memory – they express distinct patterns of pro- and anti-apoptotic Bcl-2 family members. This dynamic modulation between pro-apoptotic (Bim, Bax, and Bak) and anti-apoptotic (Bcl-2 Bcl-xL, and Mcl-1) molecules has profound biologic significance and forms a regulatory circuit that controls the survival of individual populations of T cells. Owing to these unique expression patterns, naïve, activated, and memory T cells also exhibit differential sensitivity to apoptosis, with activated T cells being most sensitive.
We have used small-molecule antagonists of Bcl-2 family members to target T cells for destruction based on activation state. One of these compound preferentially targets activated T cells and does not require Bim for cell death induction. Our preliminary data demonstrate that in vivo treatment with this small molecule antagonist completely protects mice from diabetes following adoptive transfer of diabetogenic T cells. Based on these data, we hypothesize that this protective effect stems from its preferential inhibition of Mcl-1 molecules in activated T cells. Importantly, the selectivity sensitivity of activate T cells to BH3 antagonism suggests an innovative means of attacking the current problems inherent to broad-based immunosuppression. Rather than using broad immunosuppression, unwanted auto- and allo-reactive T cells should be acutely activated, in vivo, and then differentially targeted for apoptosis using specific BH3-domain antagonists. This would spare beneficial adaptive immunity, while purging undesirable rogue T cells.
David A Hildeman, PhD
Funding: NIH R01 DK081175