Unwanted immune responses cause many diseases. The lack of beneficial responses can be blamed for many others. Despite enormous progress in unraveling how the immune system works, we rely largely on broad-spectrum immunosuppressants to treat unwanted responses and vaccines to elicit beneficial ones. New agents for suppressing harmful, and for enhancing beneficial responses are needed. The recently elucidated mechanisms of antigen recognition and T-cell activation have suggested that agents able to crosslink specific receptors on the T-cell have substantial potential for manipulating the immune response. The investigator has previously developed high affinity inhibitors of CD26, a costimulatory molecule found on CD4+ cells. This application proposes to exploit the high affinity of these inhibitors to construct multivalent agents able to crosslink specific receptors on T cells, and to test their effects on T-cell function.
The specific aims are: 1. To construct and characterize chemical agents able to crosslink CD26 and to test their effect on T-cell function. This includes determining the minimal requirements for crosslinking, costimulation, and internalization. It also includes determining if the chemical crosslinkers can costimulate naive T cells and if they can substitute for B7 costimulation of CD28. 2. To construct and characterize agents able to crosslink CD26 with the T-cell receptor (TCR), to test their effects on T-cell function, and to investigate their mechanism of action. Chemical agents able to costimulate T cells, especially naive T-cells, have potential for use in vaccine development as synthetic adjuvants, and may improve the safety, efficacy, and speed with which new vaccines can be developed. They may also prove useful for boosting immune function in immunodeficiency diseases.
Aim 2 may provide a general method for enhancing, or suppressing specific immune responses and therefore have very broad health related significance. It could lead to better agents for treating autoimmunity and thus has potential significance for multiple sclerosis, arthritis, and other autoimmune diseases, and for preventing rejection of transplanted organs.
Aim 2 could lead to better methods for eliciting specific immune responses and thus has potential application to diseases for which effective vaccines are lacking such as tuberculosis, malaria and AIDS.
