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Background Alefacept, human LFA-3/IgG 1 fusion protein, selectively reduces memory-effector (CD45RO + ) T cells, a source of the pathogenic mediators of psoriasis. Objective To evaluate the effect of alefacept on immune function, T-cell-dependent humoral responses to a neoantigen (φX174) and recall antigen (tetanus toxoid) were assessed. Methods Patients with psoriasis were randomized to the control group or to receive alefacept (7.5 mg intravenously weekly for 12 weeks). The alefacept group received φX174 immunizations at weeks 6, 12, 20, and 26 and tetanus toxoid at week 21; control subjects received φX174 at weeks 6 and 12 and tetanus at week 10. Results Mean anti-φX174 titers were comparable in both groups. There was no difference in the percentage of responders (anti-φX174 IgG ≥30% of the total anti-φX174) between the alefacept group and the control group (86% and 82%, respectively; P = .73). The percentage of patients with anti-tetanus toxoid titer increases ≥2 times baseline also was similar (alefacept, 89%; control 91%). Conclusion A single 12-week course of alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. The selective immunomodulatory effect of alefacept against a potentially pathogenic T-cell subset is associated with maintenance of a significant aspect of immune function (antibody response) to fight infection and respond to vaccinations.

Objective CD40–CD40 ligand (CD40L) interactions play a significant role in the production of autoantibodies and tissue injury in lupus nephritis. We performed an open-label, multiple-dose study to evaluate the safety, efficacy, and pharmacokinetics of BG9588, a humanized anti-CD40L antibody, in patients with proliferative lupus nephritis. The primary outcome measure was 50% reduction in proteinuria without worsening of renal function. Methods Twenty-eight patients with active proliferative lupus nephritis were scheduled to receive 20 mg/kg of BG9588 at biweekly intervals for the first 3 doses and at monthly intervals for 4 additional doses. Safety evaluations were performed on all patients. Eighteen patients receiving at least 3 doses were evaluated for efficacy. Results The study was terminated prematurely because of thromboembolic events occurring in patients in this and other BG9588 protocols (2 myocardial infarctions in this study). Of the 18 patients for whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria without worsening of renal function. Mean reductions of 38.9% (P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05) in anti–double-stranded DNA (anti-dsDNA) antibody titers were observed at 1, 2, and 3 months, respectively, after the last treatment. There was a significant increase in serum C3 concentrations at 1 month after the last dose (P < 0.005), and hematuria disappeared in all 5 patients with significant hematuria at baseline. There were no statistically significant reductions in lymphocyte count or serum immunoglobulin, anticardiolipin antibody, or rubella IgG antibody concentrations after therapy. Conclusion A short course of BG9588 treatment in patients with proliferative lupus nephritis reduces anti-dsDNA antibodies, increases C3 concentrations, and decreases hematuria, suggesting that the drug has immunomodulatory action. Additional studies will be needed to evaluate its long-term effects.

Objective To determine the immunologic effects of anti–CD40 ligand (anti-CD40L) therapy in 5 patients with systemic lupus erythematosus nephritis who participated in an open-label study of a humanized anti-CD40L monoclonal antibody. Methods Serum and peripheral blood mononuclear cells were obtained before, during, and after treatment, and the frequency of Ig and anti-DNA antibody–secreting B cells was analyzed by enzyme-linked immunospot assay and by analysis of Epstein-Barr virus (EBV)–transformed B cell lines. To determine the effect of treatment on somatic mutation of Ig genes, reverse transcriptase–polymerase chain reaction was performed on messenger RNA from 4 patients, using primers specific for the DP-47 heavy chain gene and for IgG. Finally, B cell phenotype was investigated using flow cytometry. Results Even a brief period of treatment with anti-CD40L markedly reduced the frequency of IgG and IgG anti-DNA antibody–producing B cells, and these changes persisted for several months after cessation of treatment. To confirm these findings, EBV-transformed B cell lines were screened from each of 3 patients, and a 10-fold decrease in anti-DNA antibody–secreting cell lines was found after treatment in all 3 patients. Few differences in mutation patterns were observed before and after treatment; however, the frequency of germline-encoded DP-47 sequences was significantly increased before treatment and normalized following treatment. Flow cytometric analysis of B cells revealed expansion of a CD27−/IgD− B cell subset in some of the patients, which did not change with treatment. Conclusion These are the first mechanistic studies of the effect of anti-CD40L therapy in human autoimmune disease. The results suggest that further studies of CD40L blockade are warranted.

Objective To investigate whether alefacept (a fully human lymphocyte function–associated antigen 3 [LFA-3]/IgG1 fusion protein that blocks the LFA-3/CD2 interaction) is able to reduce the signs and symptoms of joint inflammation in patients with active psoriatic arthritis (PsA). Methods Eleven patients with active PsA were treated with alefacept for 12 weeks in an open-label and explorative study. Clinical joint assessment and laboratory assessments were performed at baseline and after 4, 9, 12, and 16 weeks of treatment. Serial synovial tissue (ST) biopsy specimens from an inflamed index joint (knee, ankle, wrist, or metacarpophalangeal joint) were obtained by arthroscopy at baseline and after 4 and 12 weeks of treatment. Results At the completion of treatment, 6 of 11 patients (55%) fulfilled the Disease Activity Score (DAS) response criteria. Nine patients (82%) fulfilled the DAS response criteria at any point during the study. There was a statistically significant reduction in CD4+ lymphocytes (P < 0.05), CD8+ lymphocytes (P = 0.05), and CD68+ macrophages (P < 0.02) in the ST after 12 weeks of treatment compared with baseline. The ST and peripheral blood of those patients fulfilling the DAS response criteria contained more CD45RO+ cells at baseline and displayed a significant reduction in these cells compared with nonresponding patients. Conclusion The changes in ST, together with the improvement in clinical joint scores, after treatment with alefacept support the hypothesis that T cell activation plays an important role in this chronic inflammatory disease. Furthermore, since alefacept, a T cell–specific agent, led to decreased macrophage infiltration, the data indicate that T cells are highly involved in synovial inflammation in PsA.