Cytogenetic abnormalities involving chromosome 14 band q32 are consistently observed in human T-cell tumors. Patients with ataxia-telangiectasia (AT) are especially prone to development of these ...tumors, which frequently carry either inversion inv(14)(q11;q32) or translocation t(14;14) (q11;q32) chromosomes. We have previously shown that the cytogenetic breakpoints of one t(14;14)(q11;q32) chromosome and two inv(14)(q11;q32) chromosomes in T-cell tumors from AT and non-AT patients join the T-cell receptor α chain locus, at chromosome band 14q11, with a region(s) at 14q32 centromeric of the immunoglobulin heavy chain variable region (VH) gene IGHV. We now show that these two inv(14) breakpoints are linked by 2.1 kb of germ-line 14q32 DNA and that the three breakpoints define, by in situ hybridization analysis, a single locus at chromosome band 14q32.1 located about 15-20 million base pairs on the centromeric side of the IGH locus. Sequence analysis of the 14q32.1 breakpoint regions indicates that abnormal recombination does not universally result from mistaken V-D-J joining (D = diversity region; J = joining region). Therefore, we invoke a tumor selection model to describe the role of the 14q32.1 locus in tumor development.
The Ia antigens, encoded within the I region of the major histocompatibility complex, are a group of cell surface glycoproteins that are involved in the control of immune responsiveness. We isolated ...and determined the sequence of a 1,045-base-pair cDNA clone for one of the murine immune response genes, Eβ
k. Comparison of the predicted amino acid sequence of the product of Eβ
kwith that of Eβ
dshows that most of the amino acid differences are clustered in short stretches of peptide sequence in the first external protein domain. This clustering of allelic variation suggests that observed haplotype-specific immune responsiveness to certain antigens may be controlled, at least in part, by differences in configuration defined by these regions of allelic variability in the NH2-terminal domain of the Eβchain.
The experiments presented in this study define the molecular basis of the bm 12 mutation. Initial characterization of an alloreactive T cell clone, 4.1.4, showed this clone to recognize an ...allodeterminant present on the E beta b and A beta bm12 chains, but not on the bm 12 parent A beta b chain. To define the extent of sequence shared between the I-E beta product and the mutant I-A beta product, we isolated a cDNA clone of the E beta b gene and determined its nucleotide sequence. Comparison of the nucleotide sequences of E beta b, A beta b, and A beta bm12 shows the the A beta bm12 gene to be identical to the E beta b gene in the region where it differs from its A beta b parent. We predict that the bm 12 mutation arose by gene conversion of this region, which spans 14 nucleotides between amino acid residues 67-71 of the mature A beta chain, from the E beta b locus to the corresponding position at the A beta b locus. Recognition of this region, which spans one of the previously defined E beta allelic "hypervariable" regions, by an alloreactive T cell clone provides the first direct evidence of the functional importance of these hypervariable regions in T cell stimulation. The identification of a gene conversion event involving one of these allelic variable regions implicates conversion as a mechanism that acts on class II beta genes to create sequence diversity in regions of Ia molecules that interact with foreign antigen or a T cell receptor, regions where protein sequence polymorphism would presumably be selected for by the expanded ability it affords the organism to mount effective immune responses against a wider variety of foreign antigens.
A human T cell lymphoma has been described in which an inversion of chromosome 14 results in fusion of an immunoglobulin heavy chain VH with a T cell receptor J alpha segment, potentially resulting ...in a chimeric protein with immunoglobulin VH region recognition plus T cell receptor effector functions. Examination of the mRNA species expressed from the IgT gene in this lymphoma shows a variety of forms but all IgT mRNA include the T cell-specific exon, ET, previously located in the distal part of the VH locus. In such mRNA species, the normal leader exon of the Ig VH segment, which encodes most of the hydrophobic signal peptide, is replaced by the short ET exon encoding mainly non-hydrophobic residues. Two forms of this mRNA exist which lack the Ig VH leader sequence and thus potentially yield non-membrane proteins in the T cell lymphoma.
Ia antigens are polymorphic cell-surface glycoprotein complexes, encoded within the I region of the mouse major histocompatibility complex, that control the ability of the organism to mount effective ...antigen-specific immune responses. We have isolated and determined the nucleotide sequences of cDNA and genomic clones for the I-Eβ
sgene and we present the predicted protein sequence for most of the Eβ
spolypeptide chain. The Eβ
spolypeptide shows 95% protein homology to the other cloned Eβalleles. Comparison of the protein sequences of five Eβalleles from haplotypes that differ in responder phenotype to pigeon cytochrome c suggests that the structure of one of the Eβhypervariable regions may determine responsiveness to this antigen.
Objective
To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active ...despite treatment with MTX.
Methods
This was a multicenter open‐label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for ≥1 month with a stable, maximally tolerated dosage of oral MTX (≤20 mg/week, median dosage 15 mg/week, range 5–20 mg/week) were enrolled and received 3 mg/day tacrolimus as a single oral dose once per day for 6 months while continuing to receive MTX at the existing stable dosage. All other disease‐modifying antirheumatic drugs were discontinued; stable dosage of nonsteroidal antiinflammatory drugs and oral corticosteroids (≤10 mg/day prednisone or its equivalent) were allowed. All 80 patients received at least one dose of the study drug and were included in the primary safety and efficacy analyses. Seventy‐five patients had at least one postbaseline efficacy assessment, and 63 patients (78.8%) completed the study. The primary clinical response criterion was the American College of Rheumatology definition of 20% improvement (ACR20) at the end of treatment.
Results
Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (±SD) creatinine (Cr) level increased from 0.74 ± 0.16 mg/dl at baseline to 0.81 ± 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty‐three patients (28.8%) had a ≥30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6–63.4%).
Conclusion
In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well‐tolerated and provides clinical benefit.
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