Immune-mediated (autoimmune) human diseases are caused by antigen-reactive T lymphocytes or immunoglobulins, with variable activation of accessory effector pathways. Since antigens which trigger autoreactive lymphocytes are mostly unknown, a variety of new therapeutic approaches are directed at inhibition of lymphocyte activation, proliferation, or differentiation through use of rationally designed chimeric proteins, many containing cytotoxic moieties. Most of these agents target cell-surface receptors or antigens that are selectively expressed in antigen-presenting dendritic cells or in antigen-activated lymphocytes. For example, IL-2R or transferrin receptors and a variety of co-stimulatory counter-receptor proteins such as B7/CD28, ICAM-1/LFA-1 or CD40/CD40L are direct targets of specific agents. Much of the work preceeding the use of fusion toxins and chimeric toxins in autoimmune diseases has been based in treatment of neoplastic leukocytes (and other types of cells) with agents of this type.
This chapter reviews the biochemistry of native bacterial and plant protein toxins that have been used in therapeutic constructs. The use of fusion toxins (single polypeptide chains composed of targeting and toxic sequences) and chimeric toxins (toxin domains linked to targeting antibodies by chemical linkers, sulfhydryl bonds or high-affinity nonco-valent interactions) is then discussed. Finally, we consider a number of new chimeric proteins that could be used to treat immune-mediated diseases and which may be indirectly toxic to target cells by modification of positive/negative growth signals that regulate the balance of proliferation versus apoptosis in lymphoid cells.
196 Brigitte A. Holder and James G. Krueger References
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