Kenneth J. Hardy

The pathogenesis of rheumatoid arthritis: a guide to therapy.

&NA; The cause of rheumatoid arthritis (RA) is unknown; however, extensive research has yielded great insight into its pathogenesis. Lymphocytes play a significant role, but a lesser role in the perpetuation of late disease. The rheumatoid synovium is composed primarily of fibroblasts and monocytes that produce inflammatory cytokines, of which interleukin‐1 and tumor necrosis factor are of key importance. Potential regulatory mechanisms balancing the effects of these cytokines are inadequate to prevent joint damage and subsequent disability. These cytokines seem responsible for stimulating destructive processes in the joint via induction of prostaglandins, angiogenesis, chemo‐kines, adhesion molecules, osteoclastogenesis, and matrix metalloproteinases. This review discusses recent research findings in the immunopathogenesis of RA with respect to potential targets for therapy.

Cox-2 inhibitors: today and tomorrow.

&NA; The elucidation of inducible cyclooxygen‐ase (Cox‐2) dependent inflammatory pathways led to the development of specific Cox‐2 inhibitors, the coxibs. These agents include the currently available celecoxib and rofecoxib and such second‐generation agents as parecoxib, valdecoxib, and etoricoxib. The therapeutic advantage of coxibs is founded primarily in their lack of significant gastrointestinal (GI) side effects. Clinical trials have demonstrated the efficacy of coxibs to be completely comparable with traditional nonsteroidal antiinflammatory drugs (NSAIDs), and pharmacoeconomics suggest favorable cost/benefit ratios with these agents compared with traditional NSAIDs, related to their reduced GI complication profiles and lower indirect costs associated with disability. Although several clinical questions remain (eg, use with low‐dose aspirin, risk of thrombosis, myocardial infarction, edema, and hypertension), the emergence and clinical utility of coxibs is likely to continue on the basis of their efficacy and relative GI safety advantage. Although newer, more specific Cox‐2 inhibitors may alter the choice, it is likely that this class of anti‐inflammatories will become (if they have not already) the drugs of first choice in the treatment of acute pain, chronic pain, and most rheumatic conditions in the 21st century. In addition to the treatment of rheumatic conditions, it is possible that coxibs will also be of clinical utility in protection against malignant transformation and Alzheimer disease.

Biological Modifier Therapy for the Treatment of Rheumatoid Arthritis

&NA; The recent elucidation of pathogenic processes involving tumor necrosis factor &agr; and interleukin‐1&bgr; in the pathogenesis and persistence of rheumatoid arthritis led to the development of biological modifier agents that have had significant impact on disease severity and progression. These agents—etanercept, infliximab, and anakinra—produce a dramatic reduction in RA disease activity with relatively low toxicity compared with currently available disease‐modifying antirheumatic drugs. The main prohibition to their broader utilization is cost. The success of these agents underscores the investigative approaches to the pathogenesis of RA and the appropriate design of pharmaceutical agents to target specific proinflammatory molecules.

Donor specific bone marrow cells suppress lymphocyte reactivity to donor antigens and differentially modulate TH1 and TH2 cytokine gene expression in the responder cell population.

Previous studies have shown that post-transplantation infusion of donor specific bone marrow following a non-specific potent immunosuppressive agent such as antilymphocyte globulin (ALG) can significantly enhance graft survival compared to ALG alone. This enhancement remains variable and is thought to occur through the induction of specific partial tolerance to the renal allograft, but the underlying cellular mechanisms have not been clearly identified. In order to improve the efficacy of this specific immunosuppressive treatment and to study the events leading to enhanced allograft survival, we sought to establish a simple in vitro model based on a mixed lymphocyte reaction (MLR). We show that cellular proliferation seen in a normal MLR can be suppressed by addition of donor specific bone marrow cells (BMC). Significantly, this suppression is not observed with either third party BMC or donor specific peripheral blood mononuclear cells (PBMC). We have defined the optimum conditions of bone marrow infusion regarding number of BMC, their handling and culture, and simple enrichment procedures. Using a semiquantitative polymerase chain reaction assay, we have studied the cytokine gene expression in MLR modulated by donor specific BMC. In an unmodified allogeneic response, the responder cells show increased expression of interleukin-2 (IL-2) gamma-interferon IFN-gamma and receptor (IL-2R) mRNA, and no IL-10 mRNA. When responder cells are cultured with BMC of the stimulator, there is a 256-fold decrease in IL-2 mRNA, and a 64-fold decrease in IFN-gamma and IL-2R mRNA. There is also a 64-fold increase in IL-10 mRNA. This effect is even more marked when the BMC are depleted of CD3+ cells. The kinetics of addition of donor specific BMC to the normal allogeneic MLR culture and specificity of the action of BMC are also elucidated. Our data suggest that the enhancement of graft survival observed with donor BMC may operate through decreased proliferation of reactive T cell clones (due to decreased IL-2/IL-2R) and suppressed monocyte functions (due to decreased IFN-gamma and increased IL-10 gene expression).

Human peripheral mononuclear cells do not show proinflammatory patterns of cytokine transcription in early trauma: a preliminary report.

Injury has been hypothesized to cause inflammation through systemic release of lipopolysaccharide and pro-inflammatory cytokines, but this has proved difficult to demonstrate in humans. We looked for evidence of an inflammatory pattern of cytokine gene expression by peripheral blood mononuclear cells (PBM) in six polytraumatized patients (ISS = 25 ± 8) upon ER admission, and in six matched healthy controls. PBM tumor necrosis factor (TNF)-α, interleukin (IL)-1 β, IL-4, IL-6, IL-10, and interferon (IFN)-γ message was assessed by semi-quantitative reverse-transcription polymerase chain reaction. No increase in expression of any of the pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, or IL-6) was found after trauma, and IFN-γ tended to decrease. Of the immunosuppressive cytokines, IL-10 expression increased 5-fold (p < .05) but no change in IL-4 was discerned. This pattern is fundamentally different from the cytokine expression patterns expected with sepsis or exposure to lipopolysaccharide. These findings are inconsistent with the occurrence of systemic endotoxemia and subsequent global immunocyte activation early after trauma.

Epitope-specific signaling through CD45 on T lymphocytes leads to cAMP synthesis in monocytes after ICAM-1-dependent cellular interaction

We recently demonstrated that different CD45 monoclonal antibodies (mAb) are able to induce cellular aggregation in human peripheral blood mononuclear cells (PBMC) through LFA‐1/ICAM‐1 interactions. Such interactions could be down‐modulated by protein kinase (PK) A/G inhibitors, but were unaffected by inhibitors of PKC, suggesting the involvement of PKA or PKG in CD45 mAb‐induced adhesion. In this study we show that after incubation of PBMC with several (but not all) mAb to CD45, CD45RO and CD45RA, intracellular cAMP, but not cGMP concentrations readily increase, reaching a maximum 30 min after start of activation. As evidenced by several lines of investigation cAMP accumulation was independent of Fc receptor‐associated signaling as well as tyrosine phosphatase activity of CD45. In highly pure T lymphocytes, CD45 mAb were unable to induce cAMP synthesis, but readily did so after addition of autologous monocytes. After paraformaldehyde fixation of both quiescent or IFN‐γ/TNF‐α‐preactivated monocytes, cAMP production was no longer detectable, suggesting monocytes as the cell of origin for the increased cAMP synthesis. Further, cAMP accumulation in monocytes occurred after reconstitution to T lymphocytes preincubated with CD45 mAb and extensively washed. Importantly, pretreatment of T lymphocyte/monocyte mixtures with LFA‐1 mAb and/or ICAM‐1 mAb down‐regulated CD45 mAb‐induced cAMP synthesis. Finally, we demonstrate that CD45 mAb are not only capable of inducing cAMP production, but also of directly stimulating PKA enzyme activity. Based on the data presented, we propose that CD45 signaling in T lymphocytes subsequently activates cAMP accumulation and PKA activation in monocytes via LFA‐1/ICAM‐1‐dependent cellular interactions.