PubMed Health⌕ Search

Biomedical subjects

C O Jacob

Publications and source records attributed to C O Jacob.

At least 37 records · Page 2Linked to original sources
PubMed1993

Mechanisms of paraneoplastic syndromes of colon-26: involvement of interleukin 6 in hypercalcemia.

The precise mechanisms responsible for increased calcium levels in patients with cancer are not fully understood. In a recent study, the participation of interleukin (IL)-6 as an important mediator of key parameters of cancer cachexia in the colon-26 adenocarcinoma was reported. Here, we show that in addition to cachexia, C-26 tumour bearing mice also develop hypercalcemia. Treatment of these mice with 5' deoxyfluorouridine significantly reduces tumour size and inhibits both hypercalcemia, cachexia, and elevated serum IL-6. Moreover, monoclonal antibody to mouse IL-6 prevents both the cachexia and the hypercalcemia and reduces serum IL-6 levels in C-26 tumour bearing hosts. The administration of a bisphosphonate compound (Clodronate) reverses the hypercalcemia but has no effect on tumour burden, serum IL-6 levels, or wasting. We conclude that tumour-derived IL-6 plays a role in the pathogenesis of the C-26 associated hypercalcemia, and that the increase of serum calcium does not by itself mediate cachexia.

Adenocarcinoma↗
PubMed1993

Mouse tumor necrosis factor receptor type I: genomic structure, polymorphism, and identification of regulatory regions.

The mouse tumor necrosis factor receptor (TNFR)-I gene was cloned, sequenced, and characterized. The nucleotide sequence analysis shows that the TNFR-I is composed of 10 exons and nine introns. The first intron includes two simple dinucleotide repeat sequences, (GA)8 and (TC)9(TG)19. The (TC)9(TG)19 tandem repeat was found to be polymorphic in its length among various mouse strains. The nucleotide sequence of the 1076 bp 5' flanking region of the TNFR-I was also determined. Various possible regulatory sequences were identified in the 5' flanking region of the TNFR-I gene. For functional analysis, the 5' flanking region of the TNFR-I gene was isolated, ligated upstream of the luciferase reporter gene, and transiently transfected into L929, Hela, and a T cell hybridoma cell line. The results show that the isolated 5' flanking region has functional promoter activity and is responsible for constitutive expression of the TNFR-I gene. A series of truncated promoter constructs were generated and studied in a transient transfection system. Analysis of transient expression in L929 cells shows that the regions -1076/-939, -615/-425, and -425/-198 include positive regulatory elements, while the region -939/-615 may contain negative cis-acting elements for the constitutive expression of the TNFR-I. The shortest construct containing 198 bp of the 5' flanking region still has significant promoter activity, suggesting that the two GC-rich elements in this region may play an important role in the constitutive expression of the TNFR-I gene.

Animals↗
PubMed1992

Mechanisms of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6-mediated cancer cachexia.

In a recent report we showed that IL-6 is an important mediator of experimental cancer cachexia in the colon-26 (C-26) tumor system. In culture, on a per cell basis, C-26.IVX cell line (which develops tumors and induces severe cachexia of syngeneic hosts) produces up to 60-fold less IL-6 than single cell suspensions prepared from freshly excised tumors. In this study, the mechanism behind this observation was investigated. Analysis of the cellular composition of progressing C-26 tumors indicated they contained up to 6% of macrophages. T cells, B cells, and granulocytes were not detected in the tumors. Because C-26.IVX line grown in vitro contained no macrophages, the possibility that macrophage products may augment IL-6 synthesis by the tumor cells was tested. Indeed, IL-1 beta in a dose-dependent manner and at picogram amounts could potentiate IL-6 production by the C-26 cell line. The presence of high affinity receptors for IL-1 on the C-26.IVX cell line was established. These cells expressed approximately 1500 IL-1 sites per cell with a dissociation constant of approximately 20 pM. Next, we attempted to mimic the situation in vivo by coculture of C-26.IVX cells with syngeneic peritoneal macrophages and found that this condition gives rise to an augmented IL-6 production similar to that observed with in vivo derived tumor cells or rIL-1 beta-treated C-26.IVX cells. Furthermore, anti-IL-1 type I receptor antibody completely blocked C-26.IVX IL-6 production induced by either rIL-1 beta or by peritoneal macrophages. Taken together, these data suggest a pathway of IL-6 production by C-26 tumors that involves a cellular interaction between IL-1R-expressing tumor cells and host-derived macrophages. The results also suggest that this interaction significantly contributes to cachectic events endured by the tumor-bearing host.

Animals↗
PubMed1992

Polymorphisms in the tumor necrosis factor alpha (TNF-alpha) gene correlate with murine resistance to development of toxoplasmic encephalitis and with levels of TNF-alpha mRNA in infected brain tissue.

Murine resistance to development of toxoplasmic encephalitis (TE) has recently been mapped to the D region of the major histocompatibility complex (H-2). Since the gene for tumor necrosis factor alpha (TNF-alpha) is located 5' of the D region and TNF-alpha has been implicated as playing a role in neurological diseases, we were interested in determining the relationship of TNF-alpha production to TE resistance. We have demonstrated that resistance to TE in inbred mice can be correlated with specific restriction fragment length polymorphisms and microsatellite variants in the TNF-alpha gene. Mice that are susceptible to TE express elevated levels of TNF-alpha mRNA in brain tissue 6 wk after infection with the ME49 strain of Toxoplasma gondii. Resistant mice and all mice that are uninfected show no detectable TNF-alpha mRNA expression in brain tissue. Differences in the TNF-alpha gene between susceptible and resistant mice have been localized to the first intron, the promoter, and the 3' end of the TNF-alpha gene. These data implicate differences in regulation of TNF-alpha production in brain tissue as contributing to differences in susceptibility to development of TE.

Animals↗
PubMed1992

Definition of microsatellite size variants for Tnfa and Hsp70 in autoimmune and nonautoimmune mouse strains.

We have cloned and sequenced the upstream regulatory region of tumor necrosis factor alpha (Tnfa) gene in 12 different mouse strains and identified an allelic polymorphism in the upstream regulatory region of the mouse Tnfa gene. The TNF allele found in the NZW strain is distinct from those of all other H-2 haplotypes, supporting our previous suggestion that this allele may be associated with a regulatory or structural defect. In addition, simple tandem repeat sequences (microsatellites) within the promoter region of the Tnfa gene and the 3' untranslated region of one of the members of the HSP70 family (Hsp68c clone) were utilized as genetic markers. Ten TNF size variants and twelve HSP70 variants were identified in over forty mouse strains. Using these markers in a set of congenic mice, we mapped this member of the HSP70 family to the central portion of the H-2 complex, centromeric to the Tnfa gene. The NOD and NZW strains carry unique HSP70 alleles based on the variability in the length of this marker. These findings raise the possibility that this protein may play a role in the association of the major histocompatibility complex with these autoimmune diseases.

Animals↗
PubMed1992

Tumor necrosis factor alpha in autoimmunity: pretty girl or old witch?

The role of TNF-alpha in the pathogenesis of autoimmune disorders is poorly understood. Evidence in favor of a pathogenic role has come mainly from in vitro experiments, while in vivo studies in animal models have suggested a protective role. In this article, Chaim Jacob attempts to reconcile these apparently contradictory studies.

Animals↗
PubMed1992

Studies on the role of tumor necrosis factor in murine and human autoimmunity.

We have analyzed the roles of tumor necrosis factor alpha (TNF-alpha) in human systemic lupus erythematosus (SLE) and murine models of lupus as well as in type 1 diabetes in NOD mice. These studies suggest an important role for TNF-alpha in the pathogenesis of autoimmune disease. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of this cytokine in the genetic predisposition to SLE. The data may imply that the effect of TNF on the immune system may be more relevant to the pathogenesis of the autoimmune disease than direct local effects at some target organs. Based on the data presented, one should be cautious in extrapolating the effects of this cytokine in various in vitro systems to the in vivo situation.

Animals↗
PubMed1992

Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development.

In attempt to evaluate biological roles of tumor necrosis factor (TNF), we studied the effects of anti-TNF mAb in non-obese diabetic (NOD) mice. Anti-murine TNF mAb rendered NOD mice hypersensitive to the lethal effects of radiation and prevented the reconstitution of lethally irradiated mice with adoptively transferred lymphocytes. While TNF-alpha reduced the incidence of diabetes development in the adoptive transfer system even when given 6 days post-transfer, mAb to TNF could not reduce or increase the incidence of diabetes compared to control mice. Administration of TNF-alpha for 4 or 8 weeks significantly reduced the incidence of spontaneous insulitis in NOD mice, while anti-TNF mAb given for 8 weeks increased the incidence of insulitis significantly.

Animals↗
PubMed1992

Evidence for the involvement of interleukin 6 in experimental cancer cachexia.

In this report we describe an experimental model of cachexia that fulfills the criteria of an early effect with a small tumor mass not related to the growth rate of the tumor, and progressive wasting of muscle and fat without a detectable loss of appetite. C-26.IVX is a cell line derived from murine colon-26 adenocarcinoma which retains the transplantability of the original tumor and induces true cachexia in syngeneic hosts. Evidence is presented to support a role for interleukin (IL-6) as a cachectic factor in the development of cancer cachexia in this model system. Thus, increasing levels of IL-6 in C-26.IVX-bearing mice correlate with the development of cachexia. If the primary tumors were resected, mice gained weight and the levels of IL-6 in the serum were reduced significantly. Moreover, monoclonal antibody to murine IL-6 (but not anti-tumor necrosis factor antibody) was able to significantly suppress the development of key parameters of cachexia in tumor bearing mice.

Animals↗
PubMed1992

Tumor necrosis factor and interferon gamma: relevance for immune regulation and genetic predisposition to autoimmune disease.

The role of TNF-alpha and IFN-gamma in various models of autoimmune disease were analyzed. These include murine models of lupus, type 1 diabetes in NOD mice and the adjuvant arthritis model in rats. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement of these cytokines in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of TNF-alpha in the genetic predisposition to SLE. Based on the data presented, one should be cautious in extrapolating the effects of these cytokines in various in vitro systems to the in vivo situation.

Animals↗
PubMed1991

Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell.

MHC class II induction by cytokines has been suggested to play a major role in the initiation and propagation of immune and autoimmune processes. TNF-alpha has been found both to enhance and also to inhibit IFN-gamma-induced MHC class II expression. In the present studies, the effect of TNF-alpha on IFN-gamma induced MHC class II expression was tested in various cell lines. On the basis of the data, we propose that, depending on the stage of differentiation and maturation of the cells, TNF-alpha might synergize or antagonize the affects of IFN-gamma on the regulation of MHC class II expression. Thus, in immature cells such as HL-60 or THP-1, TNF-alpha enhances IFN-gamma-induced class II expression. However, when differentiation was induced in these cells by TPA or IFN-gamma, the additive effect of TNF-alpha on the IFN-gamma induced DR expression was eliminated. Furthermore, TNF-alpha down-regulates the IFN-gamma-induced class II expression in differentiated cells such as human skin fibroblasts or activated macrophages. In bone marrow cells induced to differentiate in vitro, TNF-alpha decreased the IFN-gamma-induced MHC class II expression in a maturation-dependent fashion. These results provide a rational explanation for the conflicting reports regarding the effect of TNF-alpha on IFN-gamma-induced class II expression. But more importantly they may be relevant to the biologic function of TNF-alpha. Thus, we show that TNF-alpha-treated mice have reduced level of Ia expression on peritoneal macrophages and in vivo treatment with TNF-alpha antagonizes the ability of IFN-gamma to induce class II expression on these macrophages.

Animals↗
PubMed1991

Tumor necrosis factor alpha in murine systemic lupus erythematosus disease models: implications for genetic predisposition and immune regulation.

Recombinant tumor necrosis factor alpha (TNF-alpha) administration significantly delayed the development of lupuslike nephritis in the New Zealand black x New Zealand white (NZB x NZW)F1 and to a lesser extent in the MRL-lpr/lpr model systems. TNF-alpha treatment was effective when treatment was initiated at 2, 3, or 4 months of age but was ineffective if initiated as late as 6.5 months of age. Treatment of (NZB x NZW)F1 mice for 3 months was more effective than treatment continued for 6 months. Anti-TNF-alpha antibodies did not develop in these mice. Flow microfluorometry analysis showed no major effects on B, T, or monocyte cell population in cells from the peritoneum, spleen, lymph node, and thymus. A decrease in class II Ia expression on macrophages in the peritoneum of TNF-alpha-treated mice was noticed. A correlation between the level of TNF-alpha inducibility in vitro and the effect of TNF-alpha administration in vivo could be shown. Although a limited polymorphism could be shown by restriction fragment length polymorphism, using an amplified (AC)n microsatellite located in the 5' regulatory region of TNF-alpha, a much more extensive interallelic polymorphism was found. The AC microsatellite allele found in NZW mice was unique and different from other lupus strains and nonautoimmune strains. These results have possible implications to the pathogenesis of systemic lupus erythematosus.

Animals↗
PubMed1990

Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus.

We report on the production of tumor necrosis factor (TNF)-alpha and TNF-beta 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 DQw1-positive donors frequently exhibit low production of TNF-alpha, whereas DR3- and DR4-positive subjects show high levels of TNF-alpha production. No correlation between TNF-alpha levels and HLA-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, DQw1-positive SLE patients show low levels of TNF-alpha 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-alpha production. DR4 haplotype is associated with high TNF-alpha inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.

Alleles↗
PubMed1990

Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1.

The role of tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-alpha were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-alpha. Treatment with TNF-alpha caused a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-alpha. Moreover, TNF-alpha was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-alpha were shared by interleukin 1 alpha in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.

Animals↗
PubMed1989

Immune response to cholera toxin epitope inserted in Salmonella flagellin.

Bacterial flagella are potent immunogens and aromatic-dependent (aro) Salmonella as live vaccines evoke humoral and cellular immune responses. Such strains expressing epitopes of protective antigens as inserts in flagellin would provide a novel way to vaccinate against diseases caused by unrelated pathogens. A synthetic oligonucleotide specifying an epitope of cholera toxin subunit B was inserted in a Salmonella flagellin gene. The chimeric flagellin functioned normally and the epitope was expressed at the flagellar surface. Parenteral administration to mice of an aro A flagellin-negative strain of S. dublin expressing the chimeric flagellin gene evoked antibody to cholera toxin.

Animals↗
PubMed1989

Heterogeneous effects of IFN-gamma in adjuvant arthritis.

In an attempt to evaluate the role of IFN-gamma in autoimmune arthritis, we tested the effects of IFN-gamma and anti-IFN-gamma mAb (DB-1) in various phases of arthritis development in a rat model for rheumatoid arthritis; the adjuvant arthritis (AA) model, induced by immunization with CFA. In addition, the effects of IFN-gamma were tested in vitro on T cell clones derived from rats afflicted with AA. T cell clone A2b, which has been shown to be arthritogenic secreted low amounts of IFN-gamma and its Ag-specific proliferation was inhibited by IFN-gamma. In contrast, clone A2c, which can inhibit the development of AA, produced high amounts of IFN-gamma and its proliferation was increased by IFN-gamma. In vivo administration of IFN-gamma 24 h before CFA caused an enhancement of arthritis, whereas giving IFN-gamma 24 to 48 h after CFA suppressed the disease. Administration of IFN-gamma between day +4 to +12 or between day +12 to +24 increased the severity of the first phase of the disease, but had no effect later. Administration of DB-1 1 to 2 days before adjuvant or between day +4 to +8 substantially decreased the disease, whereas DB-1 given from day +12 to +24 significantly enhanced it. Taken together, these results illustrate the heterogeneity of IFN-gamma in autoimmune arthritis and suggest a rational explanation for the possibly conflicting reports regarding the role(s) and effects of IFN-gamma in autoimmune processes. The multistage nature of T cell-mediated autoimmune arthritis may be due to the predominance of distinct T cell populations at different stages of the disease. The differences in the biologic activities of these T cells may be due to their patterns of lymphokine production.

Animals↗