BIOLOGIC AGENTS AND IMMUNOTHERAPY IN RHEUMATOID ARTHRITIS: Progress and Perspective
Section snippets
T-CELL DEPLETION AND INHIBITION
The rationale for evaluating T-cell directed therapies in RA has been extensively discussed previously.11, 71 Although some observers have promoted a T-cell independent model of rheumatoid synovitis, several lines of evidence support the importance of the T cell in RA: (1) CD4 T cells predominate in the early synovial lesion; (2) a purely T-cell mediated arthritis can be induced in animal models and transferred via T lymphocytes to immunologically naive animals; (3) some RA patients improve in
CYTOKINE-BASED THERAPIES
Many cytokines have closely related or overlapping effects, and induce multiple biologic responses. They can be grouped into families based on shared amino acid sequences and cells of origin. Some of these families include the hematopoietic growth factors, interferons, Ig superfamily members, and chemokines. Receptors for cytokines can also be grouped into families based on their shared association with specific signal transducing protein kinases, which may explain some overlap in cytokine
TNFa INHIBITION
The last decade has witnessed the emergence of TNFα as a critical molecule in rheumatoid synovitis. High serum levels of TNFα (cachexin) had previously been observed in patients with anorexia and weight loss from severe RA. TNFα was subsequently found at significant levels in rheumatoid synovial fluid94 and widely expressed in rheumatoid synovial tissues.22 It was also found at significant levels in supernatants from rheumatoid synovial cells in culture. TNFα induced expression of
TOLERANCE INDUCTION
Clones of T cells bearing high affinity TCRs for self-antigens (autoreactive T cells), for the most part, are deleted via apoptosis in the thymus after interaction with thymically-expressed autoantigens. Since this mechanism for deleting autoreactive T cells is not complete, remaining T cells that recognize self-antigens are controlled by at least two peripheral mechanisms of tolerance: (1) T-cell interaction with antigen occurring in the absence of necessary activation or costimulation signals
ANTI-ADHESION THERAPY
Adhesion molecules expressed on tissue cells and circulating leukocytes are thought to play a pivotal role in lymphocyte homing to lymphoid tissues, migration of leukocytes to inflammatory sites, and costimulation in cellular activation. Nearly three dozen cell surface molecules that can function as adhesion proteins have been identified and the potential role of adhesion molecules in rheumatic disorders has recently been reviewed.66 Extravasation of leukocytes is thought to occur in four
TRIMOLECULAR COMPLEX (TMC) INHIBITION
The TMC (TCR/antigen/MHC) confers specificity to immunologic reactions and is probably the most selective and proximal target for immunotherapeutics. In this context, RA is considered an antigen- or superantigen-driven process (where the antigen remains unknown) that stimulates antigen processing by APCs and interaction with T cells bearing the highest affinity TCRs, with subsequent restricted clonal activation and expansion of T cells that ignite the inflammatory cascade and fail in some way
THERAPIES DIRECTED TOWARD GROWTH CONTROL/APOPTOSIS
Increasing attention has recently been directed toward a “malignancy” model of rheumatoid synovitis, in which invasive synovial cells (particularly the synovial fibroblast-like cells found in pannus invading articular bone and cartilage) may be “transformed” by expression of oncogene products.34, 127 Synovial cells in culture and in tissue sections express a number of proto-oncogenes, which are markers of cellular activation and anchorage independence. Programmed cell death, or apoptosis, is
LESSONS FROM THE PAST AND FUTURE DIRECTIONS
What have we learned after a decade of therapeutic trials with biologic agents in patients with RA? Biologics must deliver on the promise of improved efficacy while meeting the same high standards for safety observed with current pharmaceuticals. The experience with anti-T-cell MoAbs underscores the central importance of prospective, randomized, and controlled studies (often requiring placebos) in establishing therapeutic efficacy. In addition, careful dose-escalation and dose-finding studies
ACKNOWLEDGMENTS
We would like to thank Debbie Granner for her help in the typing of the manuscript for this article.
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