Immunotolerance: mechanism and consequence

Introduction to Immunotolerence & types, mechanism, reactions

1. Immunotolerance Dr Alok Tripathi Department of Biotechnology [email protected] 3/4/2009 9:32:34 AM

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3. D efinitions 3/4/2009 9:32:37 AM

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10. ……And also….. 3/4/2009 9:32:47 AM

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15. Split Tolerance =that some part of the immune system is tolerant and some other is not. 3/4/2009 9:32:52 AM

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17. Anergy - T cells As mentioned in a previous lecture, naive T cells need co-stimulatory signals to become activated. The expression of these co-stimulatory molecules is restricted so that most tissue cells lack either B7.1/B7.2 or CD40 or both. Such cells also normally lack class II MHC molecules. Thus tissue cells normally present a spectrum of peptides from their endogenously synthesised proteins on self MHC class I in the absence of co-stimulation. Interaction of such cells with autoreactive T cells leads to the T cell becoming refractive to later encounter with the same antigen even when co-stimulation is present. This refractory state is termed anergy . 3/4/2009 9:47:35 AM

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19. Anergy - B cells As implied from the section on split tolerance, there is a mechanism for tolerising B cells to soluble antigens if they are present at sufficiently high concentration. The general rules for this tolerance mechanism were worked out using mice transgenic for rearranged immunoglobulin molecules and a transgenic soluble protein whose concentration in serum could be regulated. It is apparent that the critical parameter is receptor (surface Ig ) occupancy. When more than 5% * of the sIgM molecules are normally occupied by monomeric soluble antigen the B cell becomes anergic . This anergic state can be recognised in the case of B cells by the downregulation of surface IgM . Note the level of surface IgD remains unaffected and the precise explanation for why such B cells are refractory to stimulation even when T cell help is available is not known. 3/4/2009 9:32:55 AM

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21. In some cases there are autoreactive T cells present which are capable of reacting to their cognate antigen as presented within the host [ ie . they are not anergic or ignorant], yet do not express this reactivity in the normal intact animal. These cells appear to be prevented from reacting by the presence of other T cells, a phenomenon which has been termed Dominant Regulation or Suppression . The mechanism is again obscure, but the following experiments make it likely that this form of tolerance is at least as important as anergy . 3/4/2009 9:32:55 AM

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28. Recent experiments have shown that not only can adults be tolerised under certain circumstances, but that neonates can make effective immune responses if the antigen is presented in sufficiently immunogenic form. I believe that the supposed conflict between Matzinger and Medewar is rather 'hyped up' and essentially a matter of detail. Neonatal T cells are not intrinsically tolerisable but the systemic neonatal environment does predispose to tolerance. Nevertheless, I think that her hypothesis has drawn the attention of a wider audience to current ideas about tolerance induction and the factors determining immune responsiveness. Which of the 4 mechanisms of peripheral tolerance referred to above do you think might be inducible by inhalation of peptide? blockade of B7 (B7.1 and B7.2)? What factors can you list which would influence the effectiveness (immunogenicity) of a new subunit (purified protein) vaccine? 3/4/2009 9:32:58 AM