Properties of unresponsiveness

Further analysis of experimental tolerance systems with a variety of antigens has verified that tolerance is not only specific, but is also dose-dependent and of finite duration. Indeed, early attempts to induce tolerance with nonreplicating antigens failed in part because the initial dose of antigen did not establish a persistent state of chimerism as in the Medawar experiments or the dose of antigens was insufficient to render the host unresponsive.

Tolerance, as such, generally represents a central failure of the immune system (with the exception of active suppression) and can be transferred with lymphocytes from unresponsive hosts to irradiated recipients just as secondary responsiveness can be adoptively transferred with primed lymphocytes. This unresponsive state is manifested in both T and B lymphocytes; indeed, Chiller and Weigle in now classic experiments showed that the kinetics, dose requirements and persistence of tolerance for T and B cells were different. For example, T cell unresponsiveness is more readily induced than B cell tolerance in terms of more rapid induction kinetics and lower dose requirements. Moreover, T cell tolerance lasts longer. This may, in part, be due to the relatively-shorter half-life of B cells versus the time requirements to generate mature T cells from the thymus.

We will return briefly to (central) tolerance induction within the thymus later.

In addition, in experimental systems of tolerance induction, a small, detectable response is often obtained. When examined carefully, this response is often of low affinity for the tolerated antigen. Such a result is not surprising since the cells which would be most likely to be rendered tolerant would be those with the highest binding activity for antigen; thus, only the least avid cells would be spared. Therefore, it is not surprising that low-affinity autoantibodies can often be detected in normal human serum. These are usually of no pathological consequence and probably represent stimulation of cross-reactive clones against some extrinsic antigen that leads to a response with a low affinity for self.

It is assumed from the foregoing that tolerance represents the functional, if not physical, deletion of specific lymphocytes and that the waning of tolerance reflects the generation of new B and T cells in the absence of sufficient antigen to tolerize newly developing lymphocytes. Evidence supporting this notion has come from manipulation of either the amount of available antigen or the ability to generate new cells via the thymus.

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