Therapeutic Induction of Functional Tolerance

The therapeutic strategies available reflect a combination of corticosteroids and immunosuppressive agents, most of them acting on both T and B cells. Corticosteroids are used with the primary goal to reduce the acute inflammation and to limit tissue damage. They are also efficient in suppressing T and B cell responses, but long-term side effects are very important. Therefore, therapies normally combine corticosteroids with immunosuppressive agents in order to reduce immune responses to a level that optimally inhibits harmful immune reactions but still allows normal defense against infectious agents.

Such therapies establish a fragile balance that is helpful in some but not all autoimmune diseases. Especially the late outcome is still poorly controlled and acute relapses and chronic infections may lead to new complications such as an increased frequency of atherosclerosis, at least in some groups of immunosuppressed individuals,

This led to the development of novel strategies. They are based on either of the three principles: efficient blockade of the effector functions of immune responses, absorbing harmful immunoglobulin fractions or correction of aberrant T cell responses.

The greatest progress is currently obtained by blocking immune functions with anti-TNF-antibodies. This seems to be more efficient and better tolerated than any of the previously described immmunosuppressive agents (Feldmann et al. 1996). However, therapies based on anti-TNF-antibodies inhibit any type of immune response and therefore harbor a series of risks for patients with acute or chronic infections. Among autoimmune skin diseases psoriasis has been shown to improve under anti-TNF-therapies (Mease et al. 2000). This is an important prove of principle and we know today that this therapeutic approach can be very beneficial for our patients suffering from psoriasis, psoriasis arthritis, and acrodermatitis continua suppurativa of Hal-lopeau. In addition, neutralizing TNF may be a promising approach for acute diseases associated with inflammatory tissue destruction such as aphtous ulcers or pyoderma gangraenosum. However, we have to keep in mind that other highly effective, less invasive, and less expensive therapies are available for psoriasis.

Absorbency of harmful immunoglobulins is a logical approach that was developed from plasmapheresis. One problem is that it acts relatively late in the immune response and B cells continue to produce pathogenic immunoglobulins.

Large efforts were undertaken to develop T cell based immunotherapies. They may affect either antigen presenting cells, co-stimulation or the T cells directly. Today, strategies modulating the co-stimulation of T cells mediated through CD28/CTLA4 or LFA-2/LFA-3 seem to be one promising approach to alter autoreactive T cell responses (Abrams et al. 2000; Krueger and Ellis 2003). One other possibility would be to correct harmful cytokine production by specific T cells. Three mechanisms are under study: induction of regulatory Tr cells capable of inhibiting immune responses in an antigen-specific fashion. The second would be the deviation of harmful Th1 responses into a protective Th2 response. Such an approach may be of special interest as Th2-responses have a tendency to perpetuate and to establish an antiinflamma-tory Th2-memory, once they are initiated (Biedermann et al. 2001). Indeed, a first study performed with psoriasis patients demonstrated that IL-4 therapy is a highly effective treatment strategy for autoimmune diseases (Ghoreschi et al. 2003). The third reflects the opposite, the redirection of harmful Th2 responses into a Thl-phenotype, an approach that may be of interest in IgE-mediated diseases.

These antigen-specific T cell based approaches are still at an early clinical experimental stage and even though not appropriate for acute interventions, the first studies demonstrated that it is a very promising approach (Ghoreschi et al. 2003). For future development, these vaccination approaches are of special interest as they circumvent a series of major problems associated with all other therapies. Two important aspects are: These therapies are highly specific for the targeted antigen structure and should therefore not interfere with the other physiologically required immune responses (Rocken et al. 1996). The other is that they target the site where T cell responses are translated from the innate to the adaptive immune response and they therefore should protection of long duration.

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