On the role of a possible dialogue between cytokine and TCR-presentation mechanisms in the regulation of autoimmune disease.
Autoimmune diseases are thought to occur through some weakness in an active process of autoregulation. Two different regulatory mechanisms have been proposed separately during the years: a "non-specific" mechanism, via Th1-Th2 non-specific cytokines, and a "specific" one-on-one mechanism, via presentation of peptides, i.e., T cell receptor (TCR) peptides, by the T cells themselves. Several anti-idiotypic models rely on the latter to explain the effects of "T-cell-vaccination" therapy. We present and analyse a model for the interaction between both regulatory mechanisms within an ensemble composed of Th1 and Th2 cells. Our model shows how both TCR presentation and non-specific Th1/2 signals can cooperate in the choice of the prevailing Th1 or Th2 response. We show how TCR presentation can foster regulation, without necessitating a particular "suppressor" agent, of the type that some have assumed to play a central role in the regulation of autoimmunity. Our results suggest an important role for the cells' sensitivities to Th1 and Th2 derived cytokines; only for certain sensitivity ranges, is it possible to switch dominance between subtypes. It is argued that memory is sustained via modulation of sensitivities to cytokines, not only to antigens. The results and hypotheses also suggest one possible reason for the known correlation between standard and autoimmune diseases. Several therapies and informative experiments are suggested. We argue, for example, that administering a non-relevant peptide while increasing the ratio between the clones reactive to it and other clones in the pancreas, might cure autoimmune diabetes. Moreover, we predict that disease could be prevented by administering an autoimmune peptide at an early age while forcing the system to react in a Th2 fashion.
Bar-Or
R L
RL
Department of Applied Mathematics and Computer Science, Weizmann Institute of Science, Rehovot, Israel.
Segel
L A
LA
D000938:Antigen-Presenting Cells / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006706:Homeostasis; D006801:Humans; D018448:Models, Immunological; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D016201:Receptors, Lymphocyte Homing