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J L Hillson

Publications and source records attributed to J L Hillson.

10 recordsLinked to original sources
PubMed2000

Rofecoxib.

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.

Animals↗
PubMed1997

An unbiased analysis of V(H)-D-J(H) sequences from B-1a, B-1b, and conventional B cells.

Previous studies conclude that the repertoire of B-1a (CD5+ B) cells is highly restricted. Studies here, which use FACS sorting and single-cell PCR methodology to develop an unbiased representation of the IgH repertoires of B-1a, B-1b, and conventional B cells from the peritoneal cavity, demonstrate that the B-1a cell repertoire is more diverse than previously thought. Furthermore, adult B-1a cells have significantly fewer noncoded nucleotide (N) insertions than conventional B cells. However, B-1a cells are not defined by the absence of these regions, since such insertions are present in two-thirds of B-1a cell transcripts. All three B cell populations use a wide spectrum of V(H), D, and J(H) elements and display considerable diversity in complementarity-determining region 3 (CDR3). However, characteristic differences in the repertoires of all three B cell populations also exist, suggesting different selective and/or developmental forces act to shape each repertoire.

Animals↗
PubMed1997

Pharmacology and pharmacokinetics of methotrexate in rheumatic disease. Practical issues in treatment and design.

Methotrexate (MTX) is among the most effective drugs for treatment of rheumatoid arthritis and has been proven valuable in the treatment of multiple other disorders of immune regulation. MTX has been administered at a wide range of doses and dose intervals, in conjunction with multiple other drugs, and in patients with a broad range of concomitant disorders. To design a safe and effective MTX treatment plan for an individual patient, the provider must have knowledge of the pharmacology and drug interactions of this effective but potentially dangerous medication. The first section of the article reviews MTX structure, pharmacology pharmacokinetics, and mechanisms of action in rheumatic disease. The second section examines factors that can be used to increase MTX efficacy and decrease toxicity.

Antirheumatic Agents↗
PubMed1993

The structural basis of germline-encoded VH3 immunoglobulin binding to staphylococcal protein A.

The ability of human VH3 immunoglobulins (Ig) to bind to staphylococcal protein A (SPA) via their Fab region is analogous to the binding of bacterial superantigens to T cell receptors. The present report establishes the structural basis for the interaction of SPA and VH3 Ig. We have studied a panel of 27 human monoclonal IgM that were derived from fetal B lymphocytes. As such, these IgM were expected to be encoded by unmutated germline genes. Binding to SPA in ELISA occurred with 15 of 15 VH3 IgM, but none of 12 IgM from the VH1, VH4, VH5, or VH6 families. The VH sequences of the 27 IgM were derived from 20 distinct VH elements, including 11 from the VH3 family. Use of D, JH, and CL genes was similar among VH3 and non-VH3 IgM. A comparison of the corresponding VH protein sequences, and those of previously studied IgM, identified a probable site for SPA binding that includes VH3 residues in framework region 3 (FR3), and perhaps FR1 and 3' complementary determining region 2. The results thus demonstrate that among human IgM, specificity for SPA is encoded by at least 11 different VH3 germline genes. Furthermore, like the T cell superantigens, SPA likely binds to residues in the VH framework region, outside the classical antigen-binding site of the hypervariable loops.

Amino Acid Sequence↗
PubMed1992

Emerging human B cell repertoire. Influence of developmental stage and interindividual variation.

In B cell precursors developing in fetal lymphopoietic tissue, the selection of VH, DH, and JH gene segments for initial H chain gene assembly is biased. The present study was designed to determine whether these biases persist in fully developed human fetal B cells and to examine specificities encoded by the favored elements. B cells were prepared from two sites representing different stages of development, i.e., fetal liver as a source of cells newly generated in that lymphopoietic environment and fetal spleen as a source of more mature cells, potentially subject to selective environmental factors. The expressed repertoires were sampled by two methods. EBV transformation so binding and structure could be examined simultaneously and generation of cDNA from individual, sorted, unstimulated B cells. We found that mature B cells in liver and secondary lymphoid tissue exhibit the same degree of bias in VH use we previously reported in lymphopoietic tissue of the same gestational age. However, the pattern of DH and JH use more nearly resembled that of the adult, suggesting that some constraints imposed by the rearrangement process are normalized rapidly. Sequences recovered from EBV-transformed clones were not distinguishable from transcripts recovered from single cells by direct amplification. Among antibodies expressed by the EBV clones, binding to self-Ag was common, binding profiles varied, and, in contrast to mice, there was little relationship between specificity and VH element. Interestingly, the two individuals studied differed in the VH element most commonly used. One resembled previously studied fetal repertoires in that VH56p1 encoded about 20% of expressed antibodies, whereas the other did not express VH56p1 and used VH26 in 25% of expressed antibodies. This was found to reflect a lack of the genomic VH56p1 allele, suggesting that genetic variation at the VH locus may significantly influence the emerging human antibody repertoire.

Antibody Diversity↗
PubMed1991

Sequence analysis and idiotypic relationships of BEG-2, a human fetal antibody reactive with DNA.

Monoclonal antibody (mAb) BEG-2 is a dsDNA binding IgM lambda derived from a 12-week human fetus. Two binding site idiotypes (BEG-2 Id alpha and BEG-2 Id beta) have been defined with the use of polyclonal rabbit anti-idiotypic anti-serum. BEG-2 Id alpha is located on the lambda light chain and has been described previously. The BEG-2 Id beta is present on the mu heavy chain. By means of a direct binding ELISA, BEG-2 Id beta has been identified on EBV-derived mAbs from human fetal liver or spleen (5%), human cord blood (2.7%) and adult peripheral blood (1%). In addition, the Id is present on 8.5% of adult spleen-derived hybridoma antibodies and 6% of RA synovium-derived hybridoma antibodies. In all populations the presence of the Id is strongly associated with binding to DNA and other polyanions. Competition assays indicated that the Id was located at or near the antigen-binding site on these molecules. To explore the structural basis of this binding, a major part of the BEG-2 heavy chain was sequenced and found to be encoded by a member of the VH4 family joined to a variant of JH5 by a very short Diversity or N region. Of the BEG-2 Id beta positive mAbs for which the VH family has been determined, five are encoded by VH4 and two are encoded by VH6, but none is encoded by other families. Thus, the BEG-2 Id beta identifies a set of polyreactive antibodies that are common in fetal life, persist into adulthood and are encoded by VH6 and, a subset of VH4 genes.

Amino Acid Sequence↗
PubMed1990

Structure and evolution of mammalian VH families.

Antibodies are encoded by a limited number of germline gene segments that undergo somatic diversification through rearrangement and mutation. Because these mutation processes are efficient, it is widely believed that there is little environmental selection pressure for the maintenance of specific antibody gene sequences. We have performed pairwise comparisons of known germline (as opposed to somatically generated) antibody VH elements with the hope of identifying conserved structural features common to sets of VH gene segments. These studies reveal that VH families arose prior to the mammalian radiation and have since been conserved, that this conservation appears to reflect selection at the level of protein sequence, and that the conserved regions are discretely localized on a solvent-exposed face of the heavy chain, at some distance from the antibody combining site. A family-specific region was also identified within the recombinase recognition sequences. Our results provide a context for theories that address the physiological significance of variations in VH family utilization during the development of the immune repertoire.

Animals↗
PubMed1990

Autoantibodies and the fetal antibody repertoire.

Developing fetal B cells preferentially rearrange a restricted subset of the encoded antibody gene segments. There are striking structural similarities between elements expressed early in man and in mouse, most evident on comparison of murine VH elements from the VH7183 family to human VH elements of the VH3 family. The similarity is pronounced in two framework regions which together encode a possible binding site that is distinct from the classical antigen-combining site. By comparing all known human and murine VH gene sequences, we have demonstrated that these regions have been conserved in a family-specific manner throughout the mammalian radiation. The "non-conserved" spacer of the recombinase recognition signal is also highly conserved in a family-specific manner, suggesting a mechanism by which the expression of family-dependent features may be regulated. The evidence that such features contribute to the high incidence of self- and poly-specificity in the fetal antibody repertoire is reviewed.

Amino Acid Sequence↗
PubMed1987

Early restriction of the human antibody repertoire.

Diversification of the antibody repertoire in mammals results from a series of apparently random somatically propagated gene rearrangement and mutational events. Nevertheless, it is well known that the adult repertoire of antibody specificities is acquired in a developmentally programmed fashion. As previously shown, rearrangement of the gene segments encoding the heavy-chain variable regions (VH) of mouse antibodies is also developmentally ordered: the number of VH gene segments rearranged in B lymphocytes of fetal mice is small but increased progressively after birth. In this report, human fetal B-lineage cells were also shown to rearrange a highly restricted set of VH gene segments. In a sample of heavy-chain transcripts from a 130-day human fetus the most frequently expressed human VH element proved to be closely related to the VH element most frequently expressed in murine fetal B-lineage cells. These observations are important in understanding the development of immunocompetence.

Adult↗