Lead Inventors:
Dr. Hong Jiang,
Dr. Leonard Chess
STV Reference: IR 1979, 1779, 500
Problem or Unmet Need:
T cells play critical roles as effectors and regulators of cell-mediated immune responses. This is based upon the immune system's ability to discriminate overall T cell responses to foreign non-self antigens (protective immune responses to eliminate infectious agents) from T cell responses to intrinsic self antigens (injurious autoimmune responses potentially causing autoimmune diseases). Although many autoreactive T cells are eliminated during development in the thymus, some mature and circulate in the periphery, and are suppressed by a variety of complex regulatory mechanisms which are not fully understood.
When tolerance fails, potentially pathogenic autoimmunity can result. Conversely, aberrant induction of tolerance in T cells can impair protective immune responses. A major drawback of immunotherapeutic drugs used to treat autoimmune disorders or prevent rejection of organ transplants is unwanted suppression of protective immunity. On the other hand, normal regulatory mechanisms can lead to the immune tolerance to tumors and a verity of infectious agents under certain circumstances. This is a missing link in the treatment of tumor and ADIS patients that needs to be recognized. A more comprehensive understanding of the mechanisms, which regulate tolerance would result in more specific and effective therapeutic approaches.
Details of the Invention:
The authors established an "avidity model of peripheral T cell regulation" mediated by Qa-1/HLA-E restricted CD8+ T cells that discriminate overall T cell responses to self antigens versus to non-self, foreign antigens in the periphery. In this model, Qa-1/HLA-E restricted CD8+ T cells specifically recognize and down-regulate activation and expansion of T cell clones with intermediate avidity for their cognate peptide derived from both self and foreign antigens. Thymic negative selection deletes high avidity T cells reactive to the majority of self-antigens. The conceptual framework of the "avidity model" is based on the fact that thymic negative selection generates a truncated self-reactive T cell repertoire devoid of high avidity T cells compared with foreign reactive repertoire. Thus, selective down-regulation of intermediate avidity T cell populations containing the potentially pathogenic self-reactive T cells enables the immune system to specifically control auto-immune diseases without damaging the on going anti-infection immunity, which is, largely, mediated by high avidity T cells specific to the foreign pathogens.
Applications
• Development of therapies for autoimmunity, graft rejection, infectious disease, and allergic disorders
• Development of novel peptide-based vaccines
• Development of a new and necessary antitumor therapy to prevent the recurrence of tumors in combination with other therapies
• Development of novel diagnostic and research tools, such as assays for T cell function and animal models, to investigate and test clinical interventions
Advantages
• Allows development of novel immunotherapeutic strategies targeting previously unknown mechanisms
• Can improve current treatments for immune disorders by increasing specificity and reducing side effects
• The potential applications are numerous and include virtually every clinically relevant area of immunology research
• Permits a considerably more comprehensive understanding mechanisms of peripheral tolerance
Patent Status:
WO 2008/103471
Licensing Status: Available for Licensing and Sponsored Research Support
