Rejection - novel therapeutic targets
Costimulatory molecules, Memory T cells and Chronic rejection
Costimulatory Molecules - Studies examining the role of costimulation pathways in allograft rejection
A number of costimulatory molecules have been described (such as CD28), which play a key role in the activation of T cells. Without the signal one from the MHC-peptide interaction and the second signal from costimulatory molecules, T cells become anergic and die. OX40 (CD134) is a member of the tumour necrosis receptor superfamily and is a potent costimulatory molecule that facilitates effector T cell differentiation and survival. Although the impact of blockade of the OX40-OX40L pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined.
Current literature demonstrates that the blockade of OX40-OX40L in vivo inhibits autoreactive T cell responses, while sparing the remainder of the T cell repertoire. Thus demonstrating targeting OX40-OX40L interaction may be a beneficial strategy in autoimmune and inflammatory diseases. The role of OX40-OX40L is being investigated in a number of T cell dependent models, using both skin and cardiac transplantation. The aim of these studies is to understand the mechanisms used by OX40-OX40L interaction in the control of allograft rejection. Do naïve and memory T cells use OX40-OX40L in the same way? Are there differences in the mechanisms between T cell subsets? Would blocking OX40 be a useful adjunct therapy?
This work is in collaboration with UCB-Celltech, Slough, UK.
Memory T cells - Studies examining the role of memory T cells in graft rejection and their impact on the development of transplantation tolerance
In clinical transplantation, immunological memory poses several problems, including late graft loss or chronic rejection. Memory T cells (Tm) can develop after a rejection episode and/or as a result of viral infections where Tm that can cross react with donor alloantigens are produced. Interestingly, older recipients who have been exposed to more viruses during their lifetimes have a larger number of Tm.
Tm are often refractory to inhibition by current drug therapy and can make inducing tolerance to donor antigens much more difficult. This project is designed to investigate the cellular and molecular requirements for the development and function of CD4+ and CD8+ Tm reactive with alloantigens in vivo, information which is essential to furthering our understanding of transplant rejection. We will use these data to develop new therapeutic strategies to inhibit the functional activity of memory cells.
Vascularised solid organ transplantation has become a standard therapy for patients with end stage organ failure. With the help of modern immunosuppression acute rejection can be treated effectively when it occurs. As one year renal transplant survival approaches >90%, delayed graft loss or chronic rejection of the transplant is becoming an important problem.
Chronic rejection is a multifactorial process involving many components of the immune system as well as non-immune factors. T cells, macrophages, chemokines, pro-inflammatory cytokines and alloantibodies have all been implicated in both the initiation and progression of the rejection process. We are dissecting the cellular and molecular mechanisms that lead to the development of transplant arteriosclerosis. This knowledge will be used to develop new therapeutic strategies in order to delay or better prevent this disease.
TRIAD: Tolerance Restoration In Auto-immune Diseases
TRIG is a partner in the TRIAD consortium project which is a 3-year European Union funded collaborative research project investigating the potential for using anti-CD28 antagonist (sparing CTLA-4) for the restoration of the immune balance required for peripheral tolerance.
The objective of the study is to promote immune regulation, while specifically preventing the activation of pathogenic T lymphocytes.
By suppressing only the destructive parts of the immune system responsible, while at the same time sparing and enhancing regulatory T cells, the selective antagonist of CD28 (FR104) represents a novel drug candidate allowing specific immunosuppression to prevent, treat and/or cure T cell-mediated auto-immune diseases (AID).
An emerging theory suggests that peripheral tolerance is a balance between pathogenic T effector cells (Teff) and regulatory T cells (Treg) (1): auto-immune diseases occur if this balance is perturb and as a result leans to autoreactive cells.
The activation of T lymphocytes is under the control of costimulatory molecules that regulate differentiation into either pathogenic Teff or anti-inflammatory Treg (2). Costimulation through the CD28-B7-CTLA-4 molecular triad helps determine the balance between Teff and Treg after initial antigen exposure: CD28 leads to T cell activation, whereas CTLA-4 prevents activation and is instrumental in Treg function.
Targeting the CD28-B7 pathway in patients with B7 (CD80/86) antagonists (Orencia®, Abatacept) is a promising alternative to current immunosuppressive treatments. However, this strategy based on the inhibition of the entire pathway inhibits CTLA-4 signals crucial to the function of Treg and to the self-inhibition of autoreactive T cells. Therefore, the immune imbalance is not corrected and recovery is not achieved.
TRIAD’s approach is to selectively inhibit CD28 without impacting the regulatory interactions (CTLA-4-CD80/86 and PDL-1/CD80). In this way, we hypothesise that peripheral tolerance will be restored and activating interactions (CD28-CD80/86) will be inhibited.
As a TRIAD partner we will study the preclinical efficacy of FR104 in a model of Transplant Arteriosclerosis.
1. Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol. 2012;12(6):417-30.
2. Kinnear G, Jones ND, Wood KJ. Costimulation blockade: Current perspectives and implications for therapy. Tranplantation. 2013:in press.
For further information, please visit the TRIAD website: