The immune system usually develops antibodies and T cells that attack microbes or tumors but not our own cells or organs. However, there are circumstances where the immune system generates T cells that react and assault our own antigens and tissues. This reactivity against self could evolve into an abrupt reaction and lead to severe autoimmune disease. The long term objective of this proposal is to develop a strategy to calm the autoaggressive T cells and reverse the disease. The model system to be used to test the strategy is experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory and demyelinating disease of the central nervous system (CNS) that is used as an animal model for human multiple sclerosis (MS). In both EAE and human MS T cells infiltrate the CNS and upon recognition of the myelin proteins within the brain produce protein hormones or cytokines that attract inflammatory cells capable of destroying the myelin sheath that covers and protects the axons. A logical approach to treat this disease is to inactivate or reprogram the myelin reactive T cells to halt production of inflammatory cytokines. Peripheral and non-activated antigen presenting cells (APCs) express minimal or no costimulatory molecules. In consequence presentation of antigen by such APCs leads to T cell unresponsiveness. The strategy of antigen injection in the absence of costimulatory activation is being considered as a useful approach to turn off autoreactive T cells involved in autoimmunity. In addition, since T cells are flexible in the way that they recognize antigens it is possible to slightly modify the composition of antigen to generate altered forms that are recognizable by the T cells but could shut off the cell or reprogram the cytokine production. In this application we propose to test a vehicle strategy to deliver self and altered- self peptides in a manner that could effectively modulate the autoreactive T cells and possibly improve the disease. In this strategy wild type and modified myelin peptides will be genetically incorporated into immunoglobulins (Igs) and the resulting Ig-myelin chimeras will be injected into sick mice without adjuvant (no costimulation) to test for amelioration of the disease. We have evidence that Igs function as an efficient peptide delivery system and are endowed with the capability to promote the modulator function of altered peptides. Therefore, our hypothesis is that delivery of self and altered self peptides by Igs maybe an efficient strategy to ameliorate T cell mediated autoimmune disease involving multiple autoantigens.
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