Role of lymphotoxin in experimental models of infectious diseases: potential benefits and risks of a therapeutic inhibition of the lymphotoxin-beta receptor pathway.

Abstract

The immune system provides different mechanisms to protect organisms against pathogens, most of which are infectious agents. Simultaneously, immune activation secondary to genetic factors and/or environmental signals can induce detrimental autoimmunity. The effector pathways in host defense and autoimmunity use similar cytokines and chemokines. Accordingly, tumor necrosis factor alpha (TNF-α), for instance, is similarly important in the control of various infections and in the induction of autoimmunity. Hallmarks of the adaptive immune system are antigen-specific cellular and humoral immune responses. Secondary lymphoid organs serve as sites of contact between antigen-presenting cells (APCs) and immune effector T and B lymphocytes. Chemokines and cytokines serve as messengers determining the type of immune response to a given antigen. The TNF family cytokine lymphotoxin (LT) plays a pivotal role in the development of secondary lymphoid organs. The chronic and relapsing course of many autoimmune diseases calls for new biological agents capable of suppressing the underlying inflammatory disorders. Recent studies indicate that inhibition of LTβ receptor (LTβR)-mediated signaling in adult animals suppresses autoimmunity by modulating the cellular structure of secondary lymphoid organs (reviewed in reference 22). Because of the wide range of autoimmune diseases positively influenced by this treatment, blockade of the LTβR might serve as a new treatment principle for human autoimmune diseases. However, immune responses to infectious pathogens are also altered in mice with disrupted LTβR signaling. While the course of virus- and lipopolysaccharide (LPS)-induced shock, experimental Trypanosoma brucei infection, cerebral malaria, and experimental prion disease are less severe, inhibition of the LTβR is also associated with exacerbation of mycobacterial infection and infectious colitis. This review summarizes the findings of studies using mice with disrupted LTβR signaling in models of infectious diseases and discusses the relevance of these observations in considering LTβR blockade as a potential treatment for human autoimmune diseases.