We report on the production of tumor necrosis factor (TNF)-a and TNF-j3 by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2-and DQwl-positive donors frequently exhibit low production of TNF-a, whereas DR3-and DR4-positive subjects show high levels of TNF-a production. No correlation between TNF-a levels and HL4-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQwl-positive SLE patients show low levels of TNF-a inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-a production. DR4 haplotype is associated with high TNF-a inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQwl in SLE patients and their susceptibility to nephritis.

Class II major histocompatibility (MHC) molecules have an immunoregulatory role. These cell-surface glycoproteins present fragments of protein antigens (or peptides) to thymus-derived lymphocytes (T cells). Nucleotide sequence polymorphism in the genes that encode the class II MHC products determines the specificity of the immune response and is correlated with the development of autoimmune diseases. This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris. These findings implicate particular class II MHC isotypes in susceptibility to each disease and suggest new prophylactic and therapeutic strategies.

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)-encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQwl, and especially the rare allele DQPl.AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQP1.1, the DQPl.AZH, or the DQP1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that involves the skin, joints, serosal surface, kidneys, central nervous system, and blood elements. It is characterized by abnormalities in B cell activation, with resultant autoantibody production, and by dysregulation of T cells, the complement cascade, and the clearing of immune complexes. Genetic factors in SLE have been implicated by results of studies of family aggregation of the disease ( l ) , increased concordance of SLE among monozygotic versus dizygotic twins (2), Gm markers (3), decreased red cell CRl receptors (4), abnormal T cell suppressor function in healthy relatives of SLE patients (3, and associations with several major histocompatibility complex (MHC) loci (summarized in refs. 6 and 7).Population studies have shown an increased association between SLE and class I1 MHC DR2 and/or DR3 antigen alleles, as well as an association with class 111 MHC C2 and C4A deficiencies (8,9). The strengths of these associations vary from study to study, and they can vary in ethnically different populations (7-10). The relative risk (RR) of SLE in a person positive for any 1 of these markers has been reported to be 3 or less. However, the RR is significantly increased if multiple alleles are present, such as homozygosity of C4A null (RR = 16) or C4A null and DR2 (RR = 25) (9), which supports the notion that susceptibility to this disease may be polygenic. The class 11 loci of the human major histocompatibility complex encode the HLA-D cell-surface

Objective Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vβ3, Vβ14, and Vβ17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). Methods A double‐blind, placebo‐controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vβ3, Vβ14, and Vβ17) in IFA. A total of 99 patients with active RA received either 90 µg (n = 31) or 300 µg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. Results Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment‐related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent‐to‐treat analysis including all patients who enrolled, the 90‐µg dosage group showed a statistically significant improvement compared with control patients at the 20‐week time point after the third injection. Trends toward improvement were shown in both the 90‐µg and the 300‐µg dosage groups at week 24 after the fourth injection. Conclusion IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

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