Rheumatoid Arthritis: Yocum DE

Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. · Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore 21201, USA. · Semin Arthritis Rheum. · Pubmed #15942917 No free full text.

Abstract: OBJECTIVE: To review the benefits and risks associated with the use of the tumor necrosis factor (TNF)-blockers in various indications (eg, rheumatoid arthritis [RA], Crohn's disease [CD], psoriasis). METHODS: The members of the consensus panel were selected based on their expertise. Centocor, Inc provided an educational grant to the Center for Health Care Education to facilitate the consensus panel. Peer-reviewed articles discussing clinical studies and clinical experiences with TNF-blockers form the basis of this review. Emerging data that have not been peer-reviewed are also included. RESULTS: The TNF-blockers infliximab, etanercept, and adalimumab are all approved for treatment of RA. All 3 are effective, and there are currently no published data from head-to-head clinical trials to support using 1 agent over another. Preliminary data from small, retrospective studies indicate that switching among agents to overcome inadequate efficacy or poor tolerability is beneficial in some patients. The only TNF-blocker currently approved for the induction and maintenance of remission in CD is infliximab. Preliminary data indicate that etanercept and infliximab are effective in treating psoriasis. Some risks associated with TNF-blockers have become apparent, including congestive heart failure, demyelinating diseases, and systemic lupus erythematosus, but in most cases can be identified and managed. Several of these risks (eg, lymphoma and serious infections) are associated with either the condition per se or the concomitant medication use. Simple screening procedures help manage the risk of tuberculosis infection; however, it is recommended that physicians and patients be alert to the development of any new infection so that appropriate treatment may be initiated promptly. Rare infusion reactions, particularly with infliximab, may also be effectively managed. CONCLUSION: TNF-blockers are effective and may be safely used for short- and long-term management of RA or CD. TNF-blockers also show efficacy in other emerging indications.

Yocum DE, Castro WL, Cornett M. · Arizona Arthritis Center, University of Arizona, Tucson, USA. · Rheum Dis Clin North Am. · Pubmed #10680202 No free full text.

Abstract: Stress and pain mechanisms are complex and share many central nervous system pathways. Both are critical issues for patients with rheumatoid arthritis and other connective tissue diseases. The link between stress and neuroendoimmune function suggests that alternative therapies focusing on improved psychologic and metabolic function could significantly change patients' pain outcomes. Programs using alternative therapies such as tai chi and meditation in combination with traditional medications appear to be beneficial for patients with arthritis. These individuals appear to live better lives and may have better long-term outcomes.

Yocum DE. · Department of Rheumatology and Immunology, University of Arizona Health Sciences Center, Tucson 85724, USA. · Semin Arthritis Rheum. · Pubmed #10468412 No free full text.

Abstract: OBJECTIVES: To provide: 1) a brief review of current thought on the role of T cells in the pathogenesis of rheumatoid arthritis (RA); and 2) To provide an overview of RA therapies directed against T cells. METHODS: The following papers in relevant American and European medical journals were reviewed. Those related to: the role of T cells in the pathogenesis of RA; to biological therapy directed against cell surface markers specific to T cell populations implicated in RA; and to treatment of RA with cyclosporin A and leflunomide, pharmacological agents known to interfere with the T cell response to antigens. RESULTS: Although a variety of cell types are now recognized as contributors to the progressive joint destruction that is a hallmark of RA, T cell activation is still thought to be a central event in the initiation and progression of this disease. As a result, various therapeutic options directed against T cells have been developed. These include biological agents directed against specific populations of activated T cells and pharmacological agents that have specific T cell-modulatory actions. CONCLUSIONS: Use of T cell-directed biological therapies for RA has been disappointing, as a result of both lack of efficacy and serious toxicity. Treatment of RA with pharmacological agents that interfere with antigen-driven T cell proliferation has been more successful.

Yocum DE, Furst DE, Kaine JL, Baldassare AR, Stevenson JT, Borton MA, Mengle-Gaw LJ, Schwartz BD, Wisemandle W, Mekki QA, Anonymous00061. · University of Arizona, Tucson, Arizona, USA. · Arthritis Rheum. · Pubmed #14673984 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients. CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

St Clair EW, Cohen SB, Lee ML, Fleischmann RM, Lee SH, Moreland LW, Olsen NJ, Pratt PW, Yocum DE, Heck L, Winkelhake J, Holcenberg JS, Shulman MJ. · Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. · J Rheumatol. · Pubmed #10955324 No free full text.

Abstract: OBJECTIVE: To determine the safety and potential clinical efficacy of primary and booster injections of a DR4/1 peptide in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS. Subjects with active RA were enrolled in a randomized, placebo controlled, double blind, dose-escalating clinical trial of synthetic DR4/1 peptide containing the shared epitope. The primary injection of the DR4/1 peptide in alum adjuvant was administered at one of 3 doses, 1.3, 4.0, and 13 mg, followed by up to 3 or 4 booster injections every 6 or 8 weeks at the same dose. The primary outcomes were the occurrence of adverse effects and changes in measures of immune function. Clinical efficacy was assessed using the American College of Rheumatology 20% criteria for clinical improvement. RESULTS: Fifty-three patients were entered into the trial, including 44 who completed the study. In the absence of any observations of a dose response to the DR4/1 peptide injections, the 3 dosage groups were combined for subsequent analysis into 3 groups: patients receiving DR4/1 peptide injections every 6 weeks, patients receiving DR4/1 peptide injections every 8 weeks, and a placebo group. At all doses and each dosing interval the primary and booster injections of synthetic DR4/1 peptide were well tolerated and did not produce any significant changes in lymphocyte counts or evidence of generalized immunosuppression. Analysis of clinical efficacy showed that the 6 week group had trends toward improvement in disease measures. CONCLUSION: Primary and booster injections of the DR4/1 peptide containing the shared epitope were safe and did not broadly suppress immune function.

Yocum DE, Allard S, Cohen SB, Emery P, Flipo RM, Goobar J, Jayawardena S, Job-Deslandre C, Jubb RW, Krüger K, Lopes Vaz A, Manger B, Mur E, Nygaard H, Weiner SM, Rainer F, Sack MR, Schiff MH, Schnitzer TJ, Trigg LB, Whatmough I, Schmidt AG. · Arizona Arthritis Center, University of Arizona, Tucson, Arizona, USA. · Rheumatology (Oxford). · Pubmed #10725065 links to  free full text

Abstract: OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Flint-Wagner HG, Lisse J, Lohman TG, Going SB, Guido T, Cussler E, Gates D, Yocum DE. · Department of Kinesiology, Boise State University, Boise, Idaho, USA. · J Clin Rheumatol. · Pubmed #19279507 No free full text.

Abstract: OBJECTIVE: To assess the effects of a 16-week progressive, individualized, high-intensity strength training program on muscle strength, pain, and function in patients with rheumatoid arthritis (RA). METHODS: Twenty-four RA patients (men, n = 5; women, n = 19) receiving infliximab participated in a randomized controlled trial. The strength training (ST) group (n = 16) participated in a supervised program 3 times per week, and the control (C) group (n = 8) continued with standard of care as overseen by their rheumatologist. Assessments were completed at baseline and at weeks 8 and 16. Strength was measured by 3 repetition maximum (3RM), isometric hand dynamometer, and isokinetic dynamometer. A 100-mm visual analogue scale was used to assess pain. Functional performance was derived from a timed 50-foot walk and the Health Assessment Questionnaire Disability Index. RESULTS: The mean percent increase in strength (3RM) for the ST group from baseline to week 16 was 46.1% +/- 31.6% (P < 0.01) (mean of all three 3RM exercises: hammer curl, leg press, and incline dumbbell press), with mean gains in strength up to 4 times that of baseline values reported in all strength training exercises (upper and lower body) performed during exercise sessions. On average, right-hand grip strength increased by 2.9 +/- 4.0 kg in the ST group, in comparison with a loss of 1.2 +/- 3.0 kg in the C group over 16 weeks. The ST group had a 53% reduction in pain, in comparison with almost no change in the C group. The ST group had a significant improvement in 50-foot walk time, with a mean reduction of -1.2 +/- 1.6 seconds, in comparison with the C group (mean increase of 0.8 +/- 1.0 seconds; P = 0.01) over the 16 weeks. There was a clinically important difference (predefined as mean change +/-0.25) in the Health Assessment Questionnaire Disability Index in the ST group (-0.4 +/- 0.4) but not in the C group (-0.1 +/- 0.4). CONCLUSION: High-intensity strength training in RA patients with varying levels of disease activity and joint damage had a large, significant effect on strength, and led to improvements in pain and function, with additive patient benefits beyond the effect of their infliximab use.

Yocum DE, Conaghan PG, Olech E, Peterfy CG. · Genentech, South San Francisco, California 94080-4990, USA. · Arthritis Rheum. · Pubmed #16572438 links to  free full text

This publication has no abstract.

Tang X, Yocum DE, Dejonghe D, Nordensson K, Lake DF, Richard J. · The Department of Microbiology and Immunology, the Arizona Arthritis Center, the University of Arizona, Tucson, AZ 85721, USA. · Immunology. · Pubmed #15196219 links to  free full text

Abstract: Recently, we have described a soluble survival signal for activated lymphocytes from CD14(+) cells. As a result of the importance of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), we speculate a possible role for CD14(+) cells in supporting the outgrowth of autoreactive lymphocytes in RA. To address this issue further, supernatants from activated CD14(+) cells (CD14 cocktails) in both normal controls and RA patients were collected. The relative strength of the CD14 cocktails from normal controls and RA patients was compared. The data showed that depletion of CD14(+) cells resulted in a much higher increase of activation-induced cell death (AICD) and a decrease of lymphocyte proliferation in the peripheral blood mononuclear cells of RA patients compared to normal controls. Interestingly, CD14 cocktails from RA patients provide much stronger protection against AICD compared to those from normal controls. The observed soluble survival signal from CD14(+) cells is a general phenomenon because CD14 cocktails prevent both phytohaemagglutinin A-p- and anti-CD3-induced AICD. Furthermore, supernatants collected from human dendritic cell cultures also prevent activated lymphocytes from undergoing AICD. The data implicate an important role of the CD14(+) cell and its secreted form of survival signal in the pathogenesis of RA.

Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, Tesser J, Posever J, Miller M, Araujo J, Kageyama DM, Berry M, Karl L, Yung CM. · University of Arizona, Tucson, 85724, USA. · Arthritis Rheum. · Pubmed #15188373 links to  free full text

Abstract: OBJECTIVE: To describe a group of patients who were treated with tumor necrosis factor alpha (TNF alpha) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNF alpha antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis. METHODS: Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNF alpha antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center. RESULTS: Thirteen cases of documented coccidioidomycosis were associated with TNF alpha antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01). CONCLUSION: Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.

Yocum DE, Furst DE, Bensen WG, Burch FX, Borton MA, Mengle-Gaw LJ, Schwartz BD, Wisememandle W, Mekki QA, Anonymous00153. · University of Arizona, Tucson, USA. · Rheumatology (Oxford). · Pubmed #15014199 links to  free full text

Abstract: OBJECTIVE: To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids. RESULTS: 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints. CONCLUSION: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

Yocum DE. · Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 95724, USA. · Drugs Today (Barc). · Pubmed #12973434 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory process of unknown etiology affecting 1% of the population worldwide. It results in excess morbidity in a majority of cases and early mortality in patients with aggressive disease. Early immunohistologic studies of the rheumatoid synovium demonstrate that T-cells, especially cluster of differentiation (CD)4(+) cells, are a major component of the infiltrating inflammatory cells. It has also been demonstrated that RA patients share a common major histocompatibility complex (MHC) class II molecule, HLA-DR4. Immune activation by T-cells requires the formation of the antigen recognition complex composed of the T-cell receptor, the MHC II molecule, and antigen. Many treatment modalities for RA have targeted the T-cell and/or the antigen recognition complex. These have varied from relatively crude methods such as leukopheresis to very specific monoclonal antibodies directed toward specific T-cell antigens such as the CD4 molecule itself. Not only have these therapies been effective, but also they have provided some interesting data on the pathogenesis of RA. Unfortunately, some have been associated with harmful side effects. To date, the safest and most effective modality has been immunomodulatory drugs such as cyclosporin and FK506, either alone or in combination with other agents. It appears that the earlier these treatments are started in the course of RA, the more effective they are, not only in controlling disease but also in achieving a potential remission.

Schluter SF, Adelman MK, Taneja V, David C, Yocum DE, Marchalonis JJ. · Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA. · Cell Mol Biol (Noisy-le-grand). · Pubmed #12887102 No free full text.

Abstract: Autoantibodies directed against variable domain epitopes of the alpha/beta T cell receptor (TCR) occur in sera of man, mouse and other vertebrates. Here, we focus upon autoantibodies expressed in human rheumatoid arthritis (RA) and systemic erythematosus (SLE) with parallel studies involving collagen induced arthritis (CIA) in mice transgenic for human HLA-DR conferring resistance or susceptibility to autoimmune disease. We report specificity characterization of polyclonal and monoclonal IgM and IgG autoantibodies from SLE and for IgM monoclonal autoantibodies of RA patients. The data suggests that autoantibodies directed against "public" idiotopes present in the first complementarity determining region (CDR1) and the third framework (FR3) of the Vbeta gene products are generated in response to over-production of autodestructive T cells bearing particular Vbeta gene products and function to modulate (downregulate) the expression of these T cells. Since antibodies of these specificities are present in polyclonal IgG immunoglobulin (IVIG) preparations used for therapeutic purposes, the immunomodulatory effects of antibodies directed against TCR variable domains may account, at least in part, for the efficacy of IVIG preparations in therapy of autoimmune diseases and in the prevention of graft versus host reactions.

Robey IF, Schluter SF, Akporiaye E, Yocum DE, Marchalonis JJ. · Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA. · Immunology. · Pubmed #11985662 links to  free full text

Abstract: Natural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vbeta TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs)--OR2, OR5 and Syn 2H-11--with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.10 clone. These antibodies did not induce apoptosis in vitro, but prevented interleukin-2 (IL-2) production by antigen-specific T cells. These findings suggest an immunomodulatory function for NAAbs to TCR V-region epitopes and serve as the foundation for testing human anti-TCR mAAbs in animal models with the eventual goal of using them as therapeutic agents in human disease.

Robey IF, Schluter SF, Yocum DE, Marchalonis JJ. · Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson 85724, USA. · J Protein Chem. · Pubmed #10882168 No free full text.

Abstract: Natural autoantibodies to the T-cell receptor (Tcr) have been identified in all human sera. However, titer, epitope specificity, and isotype vary with physiological conditions, autoimmune diseases, and retroviral infections. The levels of anti-Tcr autoantibodies in rheumatoid arthritis (RA) patients are significantly higher than in normal individuals, and the autoantibodies are typically IgM. To obtain detailed information on these autoantibodies, we generated B-cell heterohybridomas secreting monoclonal IgM autoantibodies (mAAbs) from the synovial tissue and peripheral blood of RA patients. We selected clones secreting mAAbs that bound a major Vbeta epitope defined by a synthetic peptide that contains the CDR1 region of the Vbeta 8.1 gene product. From these we isolated a subset of seven mAAbs that bound a recombinant single-chain Valpha/Vbeta construct containing the peptide epitope and, also to JURKAT cells which express Vbeta 8.1. The mAAbs produced by these clones were distinct from each other in their V-region sequences. However, all the V regions were essentially identical to germline sequences in both the heavy and light chains. Heavy-chain CDR3 segments ranged in length from 17 to 26 residues, did not correspond to any known autoantibodies, and showed extensive N-region diversity in the V(D)J junctions. Five monoclonal autoantibodies use VH 3 genes, while the remaining two utilized VH 4 sequences. Light-chain variable regions used were Vkappa3 (two), Vlambda3 (four), and one Vlambda2. These autoantibodies derived their unique features from their CDR3 segments that could not be aligned with any known sequences.

Marchalonis JJ, Robey I, Schluter SF, Yocum DE. · Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson 85724, USA. · Appl Biochem Biotechnol. · Pubmed #10826947 No free full text.

Abstract: To characterize the binding specificity and light- and heavy-chain variable region usage in monoclonal human autoantibodies (mAAbs) to T-cell receptors, we constructed heterohybridomas from peripheral blood B cells of three rheumatoid arthritis (RA) patients. From a panel of more than 200 heterohybridomas secreting IgM autoantibodies binding to T-cell receptor Vbeta chain first complementarity determining segments (CDR1), we characterized two IgM/lambda molecules from a single patient in detail. These bound to both CDR1 peptide epitopes and intact TCR of recombinant single-chain T-cell receptor constructs, and to T-cell surface TCR. Spectratype analysis using epitopes mimicking a set of 24 Vbeta genes indicated that one molecule bound only a few members of the set, whereas the second showed considerable epitope promiscuity by binding to more than half of the tested CDR1 peptides. Both mAAbs used variants of a Vlambda3 gene that were very similar to one another and to the germline gene. The epitope-promiscuous autoantibody used a V(H)4 gene identical to a germline prototype, while the other incorporated a V(H)3 sequence differing in only a single residue from its germline prototype. The CDR3s of both were large and distinct from each other as well as from the corresponding segments of rheumatoid factors and "cold agglutinins" using the same or related V(H) germline genes. These mAAbs offer models for deciphering the basis of epitope promiscuity, and serve as candidates for direct use in immunomodulation because they are of intrinsic human origin and do not require molecular engineering to adapt them for use in therapy.