This proposal seeks to continue ongoing theoretical and model-building activities in the area of lymphocyte development, activation and regulation. The overall goal of the research program is to develop and refine broadly conceptual models of the immune system. There are five specific aims.
The first aim will re-evaluate differences in responses to self versus non-self vis a vis the associative recognition theory; with special attention to concerns and caveats engendered by recent findings in the area of signal transmission and lymphocyte activation pathways.
This aim focuses primarily on T cells, and is particularly directed towards two issues. First, it will determine the boundaries of the window within which incipient T cells are """"""""tolerance susceptible."""""""" This is generally predicted on the applicant's notion that tolerance is primarily delineated by time (i.e., temporally separated periods of susceptibility or signals), rather than space (i.e., availability, nature, or location of appropriate antigen presentation). In addition, this portion of this first aim hopes to deal with the problem of presented antigen density by introducing the concept of an """"""""eliminon"""""""" a """"""""patch"""""""" of presented peptides which in toto is the antigen-presenting moiety through which threshold avidity is attained. In the second aim, Dr. Cohn plan to further analyze the relationship between antigen-recognition versus effector function, to expand and refine the Protection Theory. These considerations will extend the protection hypothesis to the level of epitope recognition and density in light of the """"""""copy number"""""""" of particular specificities (VL-VH pairs). In addition, the aim includes attempts to incorporate considerations of the class (isotype) of the response, as well as issues raised by the assertion that DH reading frame plays a significant role in the selection of the B cell pool.
The third aim outlines a plan to examine the currently available data on restricted antigen recognition by T cells, in order to assess its impact on single and single-dual recognition models of the TcR. These focus on how postulated distinct sites for MHC versus processed peptide recognition might be mediated by separate sites on the TcR.
The fourth aim hopes to develop the Adaptation Theory for the determination of effector class, whereas the fifth and final aim hopes to make use of a quantitative computer system, called SIS, to allow data to be matched against theories. This will employ an automiton model. The general structure of these models uses the number of bits in a binary string to represent the number of specificities or entities under consideration. This basic set of principles is usually then applied to a grid scheme in which certain parameters are fixed and others varied. Thus, the interaction between receptor-bearing cells, presenters, antigen, etc. can be monitored. By specifying the events (e.g.; expansion of an entity, elimination of an entity), and probability of such changes based on a desired parameter, rudimentary aspects of the a model's predictions can be approximated.
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