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D M Klinman

Publications and source records attributed to D M Klinman.

139 records · Page 8Linked to original sources
PubMed1986

Oncogene expression in autoimmune and normal peripheral blood mononuclear cells.

PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases.

Autoimmune Diseases↗
PubMed1986

Effect of anti-Ia treatment on the production of anti-DNA antibody by NZB mice.

A cell transfer system was used to study the effect of anti-Ia antibodies on anti-DNA-producing B cells. B cells from autoimmune New Zealand Black (NZB) mice were necessary and sufficient to transfer anti-DNA antibody production to congenic NZB. xid recipients. Anti-Ia treatment of either donors or recipients led to a significant reduction in the number of B cells secreting anti-DNA antibody. This effect was detectable after as little as 3 days of treatment and persisted for at least 1 month after the cessation of therapy. In this system, we could find no evidence of suppressor cell induction. These data suggest that anti-Ia antibodies directly suppress autoantibody-producing B lymphocytes.

Animals↗
PubMed1985

Analysis of B-cell subpopulations. I. Relationships among splenic xid, Ly 1+, and Lyb 5+ B cells.

The phenotypic and functional relationships among the various B-cell subsets is of importance for better understanding studies of the immune system. In this report, the realm of B cells encompassed by Lyb 5, Ly 1, and xid has been examined through the use of the alloantiserum anti-Lyb 5, the unique functional properties of Ly 1+ B cells, and the spontaneous autoantibody producing congenic xid mice, NZB.xid. By functional and phenotypic analysis, we have shown that (i) Lyb 5- B cells and B cells of xid mice are largely, but not completely, overlapping; (ii) xid spleen cells contain a population which is Lyb 5+; (iii) Ly 1+ B cells fall largely in the Lyb 5+ compartment; and (iv) the autoantibody-producing Ly 1+ B cells are predominantly Lyb 5+.

Animals↗
PubMed1985

Studies of consomic mice bearing the Y chromosome of the BXSB mouse.

Previous studies have demonstrated that the Y chromosome of the BXSB mouse can lead to accelerated autoimmunity in inbred BXSB mice and in F1 hybrids. To additionally study the effects of the BXSB-Y, we have studied three sets of Y-consomic mice, NZB.BXSB-Y, NZW.BXSB-Y, and CBA/J.BXSB-Y, each consisting of background genes from the non-BXSB parent and the Y chromosome from the BXSB mouse. The effect of the BXSB-Y on autoantibody production, immunopathology, and survival was assessed. We found that the CBA/J.BXSB-Y mice showed few differences from control CBA/J males. In contrast, NZW.BXSB-Y males had accelerated renal and cardiac disease and early death, resembling that previously reported for (NZW X BXSB)F1 mice. NZB.BXSB-Y males had accelerated anti-erythrocyte autoantibodies but not accelerated anti-DNA. They lived almost as long as NZB mice. The presence of the BXSB-Y in all of the consomic mice was confirmed by crossing the consomic mice with BXSB females and demonstrating accelerated disease in the male offspring. This study demonstrates that the BXSB-Y chromosome autoimmune accelerating factor does not act alone but operates through other genes, and that the effects on different genetic backgrounds are different. The studies have implications for human lupus; they also provide a basis for future molecular biology studies of the BXSB-Y and the genes upon which it acts.

Animals↗
PubMed1985

Modulation of c-myb transcription in autoimmune disease by cyclophosphamide.

This study explores the relationship between autoimmunity and the myb proto-oncogene, a gene important for T cell development. The lpr/lpr mice had very large amounts of myb RNA in the lymph node (LN) cells; but unexpectedly, they had abnormally low levels of myb RNA in the thymus, an organ normally rich in myb RNA. Mice with the gld/gld genotype had high myb RNA levels in peripheral LN, similar to lpr/lpr mice, but had normal thymic myb RNA levels. Both lpr/lpr and gld/gld mice and an AILD patient with lymphadenopathy and high myb RNA in peripheral blood cells were treated with cyclophosphamide (CY). In all cases, the CY eliminated the lymphadenopathy and corrected the abnormal myb expression. However, there were significant differences in the clinical and cellular responses to this drug. A single large dose of CY led to marked regression of the lymphadenopathy of gld/gld mice and long-term amelioration of their autoimmune syndrome. In contrast, similar treatment of lpr/lpr mice failed to alter either the lymphadenopathy or the disease process. Consistent with these clinical findings, LN myb was normalized in gld/gld mice by a single injection of CY, whereas there was no effect on myb expression in lpr/lpr mice. The AILD patient reacted much like the gld/gld mice in that myb RNA levels in the peripheral blood, and bone marrow returned to normal after only three doses of CY. The lymphadenopathy and high levels of LN myb mRNA of the lpr/lpr mice could be normalized; this occurred only after long-term treatment with CY. These events were accompanied by an increase in thymic myb mRNA from low levels. These studies have combined a molecular probe with CY therapy to provide insights into the cellular bases for lymphoproliferative autoimmune diseases.

Animals↗
PubMed1984

Autoimmunity and increased c-myb transcription.

A single recessive gene, lpr, induces an autoimmune-lymphoproliferative syndrome in several strains of mice. The lymphoid organs of lpr/lpr mice contained cells with increased amounts of myb RNA, which codes for a protein found in the nucleus. A similar human lymphoproliferative disorder also had an increase in c-myb expression. Mouse T cells induced by mitogens to proliferate did not express large amounts of myb RNA, indicating that marked myb expression is not a general feature of lymphocyte activation and proliferation.

Animals↗
PubMed1984

Analysis of nondominant idiotypes expressed during alloimmune responses.

The antibody response of Lewis rats (RT1.A) to class I MHC antigens of the Brown Norway rat (RT1.An) was studied. Diversity of the serum alloimmune response was analyzed using syngeneic anti-idiotype raised against monoclonal antibodies of the same specificity. Cross-reactive idiotypes were detected on approximately one in one thousand Lewis anti-RT1.An serum antibodies, at concentrations ranging from 20 to 600 ng/ml. The kinetics of idiotype expression coincided with that of total anti-BN antibody production, suggesting that both were regulated by the same mechanism. To determine whether humoral anti-idiotype was involved in such regulation, sera from these animals were screened for anti-idiotype content. Using an RIA sensitive to 20 ng/ml, no humoral anti-idiotype could be detected during any phase of the alloimmune response.

Animals↗
PubMed1984

Genetic studies in NZB mice. VI. Association of autoimmune traits in recombinant inbred lines.

Because recombinant inbred lines, which are homozygous at most loci, can have any combination of parental genes, the numbers and the association of genes responsible for traits can be suggested by examining phenotypic distribution in these lines. Such studies, reported herein, uncovered two major families of nonlinked genetic loci whose interactions underlie autoimmune abnormalities in NZB mice. One family of genes leads to antibodies to murine leukemia virus, ssDNA, and erythrocytes, as well as to defective tolerance to bovine gamma-globulin. The other group of genes leads to polyclonal B cell activation, stem cell abnormalities, endogenous murine leukemia virus expression, and NTA. These studies help explain previously observed dissociations between the traits associated with these two groups of genes. Such genetic analyses provide the basis for future molecular biologic studies of the genes and gene products that underlie autoimmune disease.

Animals↗
PubMed1982

Class I major histocompatibility gene products of the brown Norway rat display two major antigenic regions.

Sixteen Lewis anti-Brown Norway monoclonal antibodies and sera from alloimmunized Lewis rats were used to study the topographic relationships of antigenic determinants on class I major histocompatibility gene products. Only two independent antigenic regions were identified in competition binding assays. The first region is composed of a set of overlapping epitopes that are conserved in class I major histocompatibility products of mice and humans, as well as rats. In contrast, the second antigenic region appears in a restricted number of inbred rat strains and is not detected in other species. The data provide serologic confirmation, at the monoclonal and serum alloantibody level, of conserved polymorphisms in the major histocompatibility gene products of different species, a finding that is consistent with the amino acid sequences of these molecules.

Animals↗
PubMed1981

Dialyzable serum components can support the growth of hybridoma cell lines in vitro.

Conditions are defined for the in vitro growth of antibody producing hybrid myeloma cell lines in an immediate environment free of non-dialyzable serum components. Continuous access to low molecular weight serum growth factors was critical to the maintenance of cell viability and antibody production. This requirement was met by use of two-chambered Marbrook vessels, whose geometry allows a small chamber containing metabolically active cells to communicate through a dialysis membrane with a large adjacent reservoir filled with serum-supplemented medium. This tissue culture technique permits the rapid isolation of proteins secreted by cells in vitro, and should permit the further definition of minimal nutritional requirements for the growth of differentiated cells in vitro.

Animals↗
PubMedDate not supplied

Abnormal numbers of cytokine producing cells in patients with polymyositis and dermatomyositis.

OBJECTIVE: To examine the constitutive pattern of cytokine production in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: PBMC secreting the type 1 cytokines IL-2 and IFN gamma and the type 2 cytokines IL-6 and IL-10 were monitored by ELIspot assay. RESULTS: The frequency of IFN gamma-secreting PBMC was reduced 2-20 fold in patients with PM and DM when compared to normal controls (p < 0.01). This change correlated inversely with disease activity (p < 0.01). PM and DM were also characterized by increased numbers of cells secreting IL-10. Patients with DM had fewer IL-2 (p < 0.03) and more IL-6 (p < 0.006) secreting cells than normal controls or patients with other myopathies. CONCLUSIONS: Abnormal patterns of cytokine production characterize patients with PM and DM.

Adult↗