Biomedical subjects

C S David

Publications and source records attributed to C S David.

At least 127 records · Page 7Linked to original sources

PubMed1994

Contrasting effects from a single major histocompatibility complex class II molecule (H-2E) in recovery from Friend virus leukemia.

Resistance to erythroleukemia induced by infection with the Friend virus complex (FV) has been mapped to several genes residing both within and outside the murine major histocompatibility complex (MHC). MHC genes located in the A, D, and Qa/Tla regions of the murine H-2 complex have been shown to affect disease resistance through their capacity to regulate various aspects of the host immune response to viral antigens. This study establishes H-2E as the fourth MHC locus controlling immunological resistance to FV. Our investigation into the role of H-2E molecules revealed two distinct and opposite effects on recovery from Friend disease. H-2b/b mice normally lack a functional E gene product and are resistant to high doses of FV. The expression of H-2E molecules in H-2 recombinant or transgenic mice of this genotype resulted in a significant decrease in spontaneous recovery from FV-induced leukemia. In contrast, H-2E expression also appeared to influence recovery from Friend disease in a positive manner, since blocking these molecules with anti-E antibodies in vivo significantly decreased recovery from Friend disease. The data indicate that the positive effects of H-2E molecules derive from their function as restriction elements for helper T-cell recognition of the viral envelope glycoprotein, and we postulate that the negative effects are due to H-2E-dependent deletion in the T-cell repertoire during development.

Animals↗

PubMed1994

Influence of deletion of T cell receptor V beta genes on the Theiler's virus model of multiple sclerosis.

To determine the role of TCR V beta genes in a model of multiple sclerosis (MS), we studied Theiler's virus infection in congenic mice with deletion of TCR V beta chromosome. Congenic mice expressing the V beta a [50% deletion of TCR V beta] or V beta c 70% deletion of TCR V beta] haplotype were generated in mice resistant [B10 (H-2b)], intermediate [B10.K (H-2k), B10.RIII (H-2r)] or susceptible [B10.S (H-2s), and B10.Q (H-2q)] to Theiler's virus induced demyelination. Deletion of TCR V beta genes (V beta a or V beta c) did not convert B10 or B10.K congenic mice to susceptibility. In contrast, congenic B10.RIII-V beta c developed prominent demyelination and 10- to 100-fold increase in virus-antigen expression in spinal cord compared to B10.RIII mice. No effect on the extent of demyelination was observed in B10.S-V beta a, B10.S-V beta c or B10.Q-V beta c mice. These experiments illustrate the critical interactions between MHC, TCR, and background genes in susceptibility to immune-mediated disease.

Animals↗

PubMed1993

Extraembryonic expression of the human MHC class I gene HLA-G in transgenic mice. Evidence for a positive regulatory region located 1 kilobase 5' to the start site of transcription.

Trophoblast, the only fetal tissue in direct contact with maternal cells, fails to express the polymorphic HLA class I molecules HLA-A and -B, but does express the nonpolymorphic class I molecule HLA-G. It is thought that HLA-G may provide some of the functions of a class I molecule without stimulating maternal immune rejection of the fetal semiallograft. As a first step in identifying the cis-acting DNA regulatory elements involved in the control of class I expression by extraembryonic tissue, several types of transgenic mice were produced. Two HLA-G genomic fragments were used, 5.7 and 6.0 kb in length. These included the entire HLA-G coding region, 1 kb of 3' flanking sequence, and 1.2 or 1.4 kb of 5' flanking sequence, respectively. A hybrid transgene, HLA-A2/G, was produced by replacing the 5' flanking sequence, first exon, and early first intron of HLA-G with the corresponding elements of HLA-A. Comparison of transgene mRNA expression patterns seen in HLA-A2/G and HLA-G transgenic mice suggests that 5' flanking sequences are largely responsible for the differing patterns of expression typical of the classical class I and HLA-G genes. Studies comparing the extraembryonic HLA-G expression levels of founder embryos transgenic for either the 5.7- or 6.0-kb HLA-G transgene showed that the 6.0-kb transgene directed HLA-G expression far more efficiently than did the 5.7-kb HLA-G transgene, producing extraembryonic HLA-G mRNA levels similar to those seen in human extraembryonic tissues. The results of these studies suggest that the 250-bp fragment present at the extreme 5' end of the 6.0-kb HLA-G transgene and absent from the 5.7-kb HLA-G transgene contains an important positive regulatory element. This 250-bp fragment lies further upstream than any of the previously documented class I regulatory regions and may function as a locus control region.

Animals↗

PubMed1993

T cell epitopes of type II collagen that regulate murine collagen-induced arthritis.

Chick type II collagen (CII), a protein commonly found in joint cartilage, induces an autoimmune arthritis when administered to susceptible strains of mice. A cyanogen bromide fragment of CII, CB11, contains the requisite epitopes critical for inducing collagen-induced arthritis. If administered as a tolerogen, however, before immunization, CB11 prevents the onset of disease. Therefore, delineation of structural elements of CB11 that can regulate autoreactive T cells became the goal of this study. To delineate the structural elements of CB11 antigenic to T cells, 14 peptides containing overlapping sequences of CB11 were generated. Mononuclear cells from CII-immunized DBA/1 mice were cultured with these peptides and the resulting supernatants examined for the production of IFN-gamma. Two peptides, CII 181-209 and CII 245-270, generated the greatest responses. The ability of these two peptides to regulate arthritis was tested by administering them to neonatal DBA/1 mice as tolerogens before immunization with CII. Both peptides suppressed the incidence of arthritis whereas no other peptide used as a tolerogen significantly altered the course of the disease. T cells from four arthritis-resistant murine strains did not recognize either peptide when immunized with CII, whereas cells from the disease-susceptible B10.Q mice responded well to both. Thus, the coincidence of T cell responses to CII 181-209 and CII 245-270 in CIA-susceptible mice and the lack of response in disease-resistant strains or CII-tolerized mice identify these two peptides as containing important T cell epitopes that regulate CIA.

Amino Acid Sequence↗

PubMed1993

Human class I major histocompatibility complex transgene prevents virus-induced demyelination in susceptible mutant B10.D2dml mice.

Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelination in susceptible strains of mice, providing an excellent model for multiple sclerosis. Class I genes within the major histocompatibility complex locus (H-2D region) play a major role in determining whether strains of mice develop chronic demyelination and TMEV persistence. B10.D2dml mice with deletion in the 3' end of Dd and the 5' end of Ld genes develop the most prominent demyelination in comparison with resistant B10.D2 mice with normal complementation of H-2D region genes. We tested whether expression of a class I human transgene (HLA-B27) would modulate virus-induced demyelination in mutant B10.D2dml mice. Transgenic B10.D2dml (HLA-B27+) mice infected with virus showed dramatic decrease in the extent of demyelination (p < 0.0001) and virus antigen expression in spinal cord compared with littermate controls without the human class I transgene. These experiments demonstrate that transgenic expression of a human class I major histocompatibility complex locus molecule can prevent demyelination induced by a virus in mutant mice.

Animals↗

PubMed1993

Genomic organization and tissue expression of the mouse proteasome gene Lmp-7.

LMP7 is one of the two proteasome subunits encoded in the major histocompatibility complex and is speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Here we report the genomic organization of the mouse Lmp-7 gene and the tissue distribution of its messenger RNA. In contrast to human LMP7 which is composed of seven exons and six introns, the mouse Lmp-7 gene is organized in six exons and five introns. Interestingly, the region corresponding to the first exon of human LMP7 is highly modified by numerous insertions and deletions and contains two in frame stop codons. Consequently, the mouse Lmp-7 gene does not allow the alternative exon usage described in humans and most likely encodes for only one LMP7 protein. Thus, the Tap-1 3' end gene region and the Lmp-7 initial translation codon are separated by an 1182 nucleotide region which contains a TATA-box, a cAMP regulatory element, two SP1 sites, and two G-C-rich regions. Expression of the Lmp-7 messenger RNA was analyzed on different tissues from unstimulated mice. Lmp-7 messenger RNA is expressed in spleen, thymus, lung, liver, heart, and, at a very low level, in kidney but not in brain and testis. The possible role of Lmp genes in antigen processing is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Prevention of collagen induced arthritis in mice by deletion of T cell receptor V beta 8 bearing T cells with monoclonal antibodies.

Collagen induced arthritis (CIA) is an animal model of inflammatory polyarthritis. Immunotherapy with the monoclonal antibody F23.1, which deletes V beta 8 bearing T cells, significantly decreased the incidence of CIA in mice. Treatment with the monoclonal antibody 466B5, to delete V beta 6 bearing T cells in combination with F23.1 was no more effective than F23.1 alone and the CIA incidence in 466B5 treated animals was not significantly different from controls. Thus, the V beta 8 family of T cell receptor is expressed on self-reactive T cells in the CIA model of B10.RIII mice injected with porcine type II collagen.

Animals↗

PubMed1993

T-cell receptors and collagen induced arthritis in H-2r mice.

Mouse strains B10, B10.RIII, RIIIS/J and the F1 and backcross progeny arising from them were tested for susceptibility to porcine type II collagen-induced arthritis (PII-CIA). The clinically severe arthritis of rapid onset that is characteristic of PII-immunized B10.RIII mice developed predominantly in hybrid offspring that had inherited at least one copy of wild type T cell receptor (TCR) genes (V beta b genotype) from the B10 or B10.RIII parent. The results indicate that, in the development of PII-CIA, mice expressing the H-2r/r haplotype preferentially utilize TCR V beta genes that are normally encoded within the TCR V beta genomic deletion region of RIIIS mice (V beta c). After aggressive immunization with PII, the use of alternative TCR V beta genes, encoded outside of the RIIIS deletion region, produced a high IgG antibody response that was cross-reactive with mouse type II collagen (MII) and equivalent to that of B10.RIII mice, but only a very mild, late onset arthritis of 56% (27/48) incidence in RIIIS male mice and 28% (10/35) incidence in RIIIS female mice. In comparison, B10.RIII mice routinely developed early onset of PII-CIA of significantly higher incidence (100%; p < 0.005) and four-fold greater severity, even after milder immunization protocols. The data are compatible with the proposal that the clinically weak CIA response of RIIIs mice may be primarily antibody driven while the severe CIA of B10.RIII mice reflects the added inflammatory effects of collagen-reactive effector-T cells in the joint.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Expression of MHC class II A alpha k transgene. Pairing with endogenous beta-chain is dependent upon affinity and competition.

Studies on cell lines transfected with MHC class II genes have revealed important limitations on the assembly of haplotype-mismatched A alpha/A beta complexes. We have investigated pairing restriction in vivo by analyzing transgenic mice that carry an A alpha k gene on several H-2 haplotypes. Previously, we reported the A alpha k transgenic expression on the cell surface of H-2b and H-2u strains. Further transcomplementation studies performed with high A alpha k-expressing transgenic lines revealed that A alpha k chain can pair with A beta b,s,f,d,v, or u chains but not with A beta q. Homozygosity for the A alpha k transgene increased the expression of mixed heterodimers. The inefficient assembly of haplotype-mismatched class II polypeptides results from their inability to compete with the matched pairs. The higher affinity between the matched pairs can be overcome by increased synthesis of the mismatched pair. Thus, there is no "strict" sequence-based restrictions on pairing.

Animals↗

PubMed1992

Spontaneous recovery from Friend retrovirus-induced leukemia. Mapping of the Rfv-2 gene in the Q/TL region of mouse MHC.

The Rfv-2 gene that influences the rate of spontaneous recovery from erythroleukemia induced by a low dose of Friend retrovirus complex was mapped to the Q/TL region of mouse MHC. Rfv-2 was physically and functionally distinct from the I-A-linked Ir gene that has been shown to control the responsiveness of Th cells to the envelope glycoprotein of Friend murine leukemia helper virus. The negative effect of the Rfv-2s allele was overcome by the B10.D2-H-2dm1 mutation of the D-L genes of H-2, suggesting functional similarities between the D-L and Q/TL genes in influencing resistance against Friend murine leukemia retrovirus complex infection or possible modification of Q/TL expression by genes in the D-L region.

Animals↗

PubMed1992

Restricted heterogeneity in T-cell antigen receptor V beta gene usage in the lymph nodes and arthritic joints of mice.

We have used PCR to study the expression of T-cell antigen receptor beta RNA containing particular variable region (V) elements from transcripts directly in the cells isolated from joints and lymph nodes of B10.Q mice (H-2q) immunized with chicken type II collagen. Our data show that the T cells present in arthritic joints expressed only a few V beta transcripts--V beta 2, -6, -7, -8.2, -9, -10, and -15. V beta 6 and -8.2 were expressed predominantly (six out of seven animals) while others were expressed at a relatively low level in different animals. In lymph node cells, transcripts for V beta 6, -8.2, and -9 were detected in four out of seven animals. The data indicate that in collagen-induced arthritis there is a restrictive usage of TCR V beta elements and that V beta 6 and -8.2 are probably used preferentially.

Animals↗

PubMed1992

Role of T cell receptor V beta genes in Theiler's virus-induced demyelination of mice.

Intracerebral infection of certain strains of mice with Theiler's virus results in chronic immune-mediated demyelination in spinal cord. We used mouse mutants with deletion of the V beta class of TCR genes to examine the role of TCR genes in this demyelinating disease which is similar to multiple sclerosis. Quantitative analysis of spinal cord lesions demonstrated a markedly increased number and extent of demyelinated lesions in persistently infected RIII S/J mice which have a massive deletion of the TCR V beta-chain (V beta 5.2, V beta 8.3, V beta 5.1, V beta 8.2, V beta 5.3, V beta 8.1, V beta 13, V beta 12, V beta 11, V beta 9, V beta 6, V beta 15, V beta 17) compared with B10.RIII mice which are of identical MHC haplotype (H-2r) but have normal complement of V beta TCR genes. In contrast, infection of C57L (H-2b) or C57BR (H-2k) mice which have deletion of the V beta TCR genes (V beta 5.2, V beta 8.3, V beta 5.1, V beta 8.2, V beta 5.3, V beta 8.1, V beta 13, V beta 12, V beta 11, and V beta 9) resulted in few demyelinating lesions. Genetic segregation analysis of (B10.RIII x RIII S/J) x RIII S/J backcrossed mice and (B10.RIII x RIII S/J) F2 mice demonstrated correlation of increased susceptibility to demyelination with deletion of TCR V beta genes. The increase in number of demyelinating lesions correlated with increase in number of virus-Ag+ cells in spinal cord. These experiments provide strong evidence that the structural diversity at the TCR beta-complex can influence susceptibility to virus-induced demyelination.

Animals↗

PubMed1992

HLA-DQ beta chain can present mouse endogenous provirus MTV-9 product and clonally delete Tcr V beta 5+ and V beta 11+ T cells in transgenic mice.

The elusive Mls gene(s) are mouse mammary tumor virus genes. The endogenous cotolerogen involved in the clonal deletion of Tcr V beta 5.1, 5.2, and 11 in H-2E+ mouse strains has been narrowed down to MTV-9. We demonstrate that similar to H-2E alpha molecules, human DQw6 beta chain mediated clonal deletion of Tcr V beta 5.1, 5.2, and 11 also requires the MTV-9 gene product. This shows that human class II molecules can present mouse retroviral antigen. Further, backcross analysis involving [B10.M(DQb) x DBA/1] suggest a second cotolerogen in the B10.M background in the clonal deletion of V beta 5-bearing T cells.

Animals↗

PubMed1992

Expression of HLA-B27 in transgenic mice is controlled by gene(s) mapping between H-2D and H-2L loci.

The level of HLA-B27 transgene expression on the cell surface is dependent on the host H-2 haplotype. Mice homozygous for the H-2b, H-2f, H-2s, H-2p, H-2r, and H-2k haplotypes express B27 at high levels. An intermediate level of B27 expression is observed in H-2v mice whereas low levels of B27 are expressed in H-2q and H-2d mice. The decreased expression of B27 maps to the D region of the major histocompatibility complex. Recombinant strain B10.RKDB (DdLb) mapped the low expression gene centromeric to H-2L. In order to determine the low expression within the H-2D region, the B27 transgene was introduced into B10.D2-H-2dm1 and BALB/c-H-2dm2 mice. Expression of B27 in both of these strains was high indicating that neither H-2Dd nor H-2Ld is responsible for the low expression. This maps the effect between the H-2D and H-2L loci. In addition, introduction of human beta 2-microglobulin (beta 2m) into B10.D2-B27 transgenic mice caused a marked enhancement of B27 expression on the cell surface suggesting that the defect in B27 expression in certain haplotypes is due to an inability of B27 to associate with endogenous mouse beta 2m. We propose that gene(s) mapping between D and L (either D2, D3, D4, or some as yet unidentified gene) may be involved in class I assembly by helping association of beta 2m with class I. This putative molecule, designated "Assembly Enhancer (AE)" might have a negative influence in the association between human class I and mouse beta 2m.

Animals↗

PubMed1992

PFGE mapping and RFLP analysis of the S/D region of the mouse H-2 complex.

We have constructed a long range restriction map of the S/D segment of the mouse H-2 complex by pulsed field gel electrophoresis and hybridization with mouse cDNA probes to Bf and Tnfa genes and human cDNA probes to BAT2, BAT3, BAT4, BAT5, and BAT6 genes which have recently been mapped to the human HLA complex between C2 and HLA-B. The distance between the mouse C2 and Tnfa genes was found to be approximately 350 kilobases. The position of the mouse Bat genes in this map were found to be comparable to the position of the BAT genes in the human HLA complex. A panel of recombinant mouse strains was also examined by restriction fragment analysis with probes detecting the Hsp70, Bat5, and Tnfa genes. The results indicate that recombination in this segment is not random. No recombinants were found with crossovers between the C2 and Hsp70 genes and only one recombinant was found with a crossover between Tnfa and H-2D. In contrast, the crossover sites of 16 recombinants were mapped between the Hsp70 and Tnfa genes. Seven of these recombinants were found to have crossovers between Hsp70 and Bat5 and three recombinants were found to have crossover sites between Bat5 and Tnfa.

Animals↗

PubMed1992

I-A alpha k transgene pairs with I-A beta b gene and protects C57BL10 mice from developing autoimmune myasthenia gravis.

The I-A beta gene has been implicated in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), with amino acids at positions 67, 70, and 71 of the I-A beta b chain that play a crucial role. In addition, the cell surface expression of the I-E molecule in C57BL10.E alpha k transgenic mice was associated with the partially suppressed serum anti-acetylcholine receptor antibody and clinical expression of EAMG. In this study, the contribution of the I-A alpha gene and the A beta b:A alpha k transpair in EAMG pathogenesis is assessed. The I-A alpha k transgene was introduced into the B10 (A beta b:A alpha b) strain, and the I-A alpha k chain was paired with I-A beta b; therefore, the A beta b:A alpha k complex was expressed on the cell surface. Expression of the A beta b:A alpha k transpair in C57BL10 transgenic mice suppressed the cellular and humoral autoimmune responses to acetylcholine receptors (AChR), reduced the amount of muscle AChR bound with antibody, and significantly reduced the incidence of muscle weakness and its associated abnormal electrophysiological response.

Animals↗

PubMed1992

Heteroconjugate antibodies enhance cell-mediated anti-herpes simplex virus immunity in vivo.

Heteroconjugate antibodies are generated by covalently linking two mAbs with different specificities. When anti-CD3 mAb, capable of activating effector T cells, is coupled to anti-herpes simplex virus (HSV) mAb, which binds HSV antigens on virally-infected target cells, the resulting heteroconjugate antibody can be used in vitro to enhance anti-HSV immunity. Specifically, these heteroconjugate antibodies can augment anti-HSV immunity among lymphocytes previously lacking cytotoxicity against HSV-infected target cells. However, the efficacy of these specialized reagents in enhancing anti-HSV immunity in vivo has not been determined. We report here that anti-HSV heteroconjugates used in an adoptive transfer murine model of HSV-1 infection inhibited HSV replication in vivo and improved long-term survival. These results demonstrate that heteroconjugate antibodies have a potential therapeutic role in enhancement of anti-HSV immunity.

Animals↗

PubMed1992

Determination of tolerance to self E alpha peptides by clonal elimination of H-2E reactive T cells and antigen presentation by H-2A molecules.

A series of three synthetic peptides spanning H-2E alpha k chain residues (90-110), (110-130), and (130-150) were synthesized and purified. Mice representative of H-2E- (B6, B10, B10.M, B10.Q, B10.S) and H-2E+ (B10.D2, B10.K, B10.RIII) were immunized with individual peptides and lymph node cells challenged in vitro. Both B6 and B10 mice respond to in vitro challenge to peptides (90-110) (cpm 20,000), (110-130) (cpm 40,000), and (130-150) (cpm 60,000). In contrast all H-2E+ haplotypes were unresponsive to all three peptides (cpms < 10,000). Furthermore, B10 mice could be rendered hyporesponsive to E alpha k peptide challenge following expression of an E alpha k transgene or mating to an H-2E+ strain. The H-2Ad,k,f,q,s alleles were associated with reduced peptide recognition. Furthermore, alteration of the H-2A beta chain in bm12 mutant mice resulted in impaired responses to all three peptides. Immunization with synthetic peptides comprising major histocompatibility molecules may yield insights into mechanisms of self-tolerance.

Amino Acid Sequence↗