Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.
Pro-inflammatory CD4(+) T-cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen-presenting cells presenting self antigen to self-reactive interferon-gamma and interleukin-17-producing CD4(+) T-helper (Th) type 1/Th17 cells. To date, the majority of Food and Drug Administration-approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments, which allow for the directed blockade of the deleterious effects of self-reactive immune cell function. According to the two-signal hypothesis, activation of a naive antigen-specific CD4(+) T cell requires both stimulation of the T-cell receptor (TCR) (signal 1) and stimulation of costimulatory molecules (signal 2). There also exists a balance between pro-inflammatory and anti-inflammatory immune cell activity, which is regulated by the type and strength of the activating signal as well as the local cytokine milieu in which the naive CD4(+) T cell is activated. To this end, the majority of ongoing research is focused on the delivery of suboptimal TCR stimulation in the absence of costimulatory molecule stimulation, or potential blockade of stimulatory accessory molecules. Therefore, the signaling pathways involved in the induction of CD4(+) T-cell anergy, as apposed to activation, are topics of intense interest.
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Joseph R
JR
Podojil
Stephen D
SD
Miller
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002986:Clinical Trials as Topic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D011494:Protein Kinases