Biomedical subjects

R Noelle

Publications and source records attributed to R Noelle.

7 recordsLinked to original sources

PubMed1998

Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage.

Mcl-1 is a member of the Bcl-2 family that is expressed in early monocyte differentiation and that can promote viability on transfection into immature myeloid cells. However, the effects of Mcl-1 are generally short lived compared with those of Bcl-2 and are not obvious in some transfectants. To further explore the effects of this gene, mice were produced that expressed Mcl-1 as a transgene in hematolymphoid tissues. The Mcl-1 transgene was found to cause moderate viability enhancement in a wide range of hematopoietic cell types, including lymphoid (B and T) as well as myeloid cells at both immature and mature stages of differentiation. However, enhanced hematopoietic capacity in transgenic bone marrow and spleen was not reflected in any change in pool sizes in the peripheral blood. In addition, among transgenic cells, mature T cells remained long lived compared with B cells and macrophages could live longer than either of these. Interestingly, when hematopoietic cells were maintained in tissue culture in the presence of interleukin-3, Mcl-1 enhanced the probability of outgrowth of continuously proliferating myeloid cell lines. Thus, Mcl-1 transgenic cells remained subject to normal in vivo homeostatic mechanisms controlling viable cell number, but these constraints could be overridden under specific conditions in vitro. Within the organism, Bcl-2 family members may act at "viability gates" along the differentiation continuum, functioning as part of a system for controlled hematopoietic cell amplification. Enforced expression of even a moderate viability-promoting member of this family such as Mcl-1, within a conducive intra- and extracellular environment in isolation from normal homeostatic constraints, can substantially increase the probability of cell immortalization.

Animals↗

PubMed1997

Blockade of CD40 ligand-CD40 interaction impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation.

Alloreactive T cells require costimulatory signals via CD40 ligand (CD40L). The tissue-destructive properties of allogeneic CD4+ but not CD8+ T cells were inhibited by anti-CD40L mAb. Fewer CD4+ thoracic duct lymphocytes (TDL) were obtained in mAb-treated recipients. Kinetic studies revealed that CD4+ T cell expansion was reduced or delayed which may account, in part, for the partial graft-vs-host disease protective effect of anti-CD40L mAb. TDL were found to have diminished anti-host-specific proliferative responses. The frequency of donor TDL and splenocytes that expressed the Th1 cytokines IL-2, IL-12 p40, and IFN-gamma mRNA was markedly diminished in mAb-treated recipients, demonstrating that Th1-driven alloresponses were susceptible to CD40L targeting. Perforin mRNA-expressing T cells were undetectable in mAb-treated recipients, consistent with reduced in vivo lethality after the adoptive transfer of allogeneic CD4+ T cells. Similar findings were observed in both B cell-replete or -deficient recipients, indicating that allogeneic T cell expansion and priming can be sustained by a non-B cell, CD40+ host cell population. Mice receiving CD40L-deficient allogeneic CD4+ T cells had survival rates comparable to the rates of those given anti-CD40L mAb treatment. Because anti-CD40L mAb also was found to prevent host anti-donor-mediated marrow allograft rejection, in vivo blockade of CD40L-CD40 interactions may provide a highly beneficial approach to improving the outcome of allogeneic bone marrow transplantation.

Animals↗

PubMed1996

Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2 mediated autoimmune disease.

We assessed the role of CD40-CD40L, cytotoxic T lymphocyte (CTL)A4/CD28-B7s, and CD2-CD48/CD58 lymphocyte costimulatory pathways in the development of mercury chloride (HgCl2)-induced autoimmune disease in mice, which is believed to be mediated by T helper (Th) subset Th2. Inhibition of CD40-CD40-L and CTLA4/CD28-B7s interactions by anti-CD40-L antibody and soluble CTLA4-immunoglobulin (Ig) fusion protein, respectively, abrogated the autoimmune disease without affecting interleukin 4 (IL-4) production, showing the importance of physical contact between T and B lymphocytes in the Th2-mediated process. In contrast, two anti-CD2 antibodies that have been shown to induce immunosuppression of Th1-mediated events exacerbated the autoantibody response and augmented IgG1, IgE, and IL-4 production, transforming a mild mesangial glomerulopathy into a severe systemic immune complex disease. These observations demonstrate that manipulation of lymphocyte accessory counterreceptor interactions may affect the course of Th2-associated autoimmune disease and suggest that signals resulting from CD2 engagement play an essential role in the regulation of the Th1-Th2 effector equilibrium.

Animals↗

PubMed1995

Cartography of ribosomal proteins of the 30S subunit from the halophilic Haloarcula marismortui and complete sequence analysis of protein HS26.

By two-dimensional polyacrylamide gel electrophoresis of 30S ribosomal subunit proteins (S proteins) from Haloarcula marismortui we identified 27 distinct spots and analyzed all of them by protein sequence analysis. We demonstrated that protein HmaS2 (HS2) is encoded by the open reading frame orfMSG and has sequence similarities to the S2 ribosomal protein family. The proteins HmaS5 and HmaS14 were identified as spots HS7 and HS21/HS22, respectively. Protein HS4 was characterized by amino-terminal sequence analysis. The spot HS25 was recognized as an individual protein and also characterized by sequence analysis. Furthermore, the complete primary sequence of HS26 is reported, showing similarity only to eukaryotic ribosomal proteins. The sequence data of a further basic protein shows a high degree of similarity to ribosomal protein S12, therefore, it was designated HmaS12. Slightly different results compared to published sequence data were obtained for the protein HS12 and HmaS19. The putative 'ribosomal' protein HSH could not be localized in the two-dimensional pattern of the total 30S ribosomal subunit proteins of H. marismortui. Therefore, it seems to be unlikely that this protein is a real constituent of the H. marismortui ribosome.

Amino Acid Sequence↗

PubMed1995

Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses.

Interactions between T and B cells are dynamic and regulated by interacting receptor: co-receptors. Interactions between CD40 and its ligand, gp39, and the CD28/CTLA-4 and B7 family members play a decisive role in regulating the progression of cognate interactions. The interdependence of gp39-CD40 and CD28/CTLA-B7 expression and function was studied in vitro during an antigen-induced immune response using T cells from mice expressing a transgenic T cell receptor (TCR). gp39 was induced on pigeon cytochrome c (PCC)-transgenic T cells in the presence of antigen and antigen-presenting cells. The antigen-induced expression of gp39 on transgenic T cells was inhibited by antibodies to class II major histocompatibility complex, CD4 and LFA-1, but not by CTLA-4 Ig, anti-B7-1 or anti-B7-2. These data established that the antigen-induced expression of gp39 was not dependent on co-stimulation via CD28/CTLA-4. The addition of PCC also resulted in the modest expression of B7-1 and a more robust expression of B7-2 on the cognate B cells. The addition of anti-gp39 blocked the up-regulated expression of B7-1 and partially blocked the up-regulated expression of B7-2. The addition of anti-gp39 and anti-interleukin-4 inhibited antigen-induced expression of B7-2 on B cells to near background levels. Studies on the up-regulation of B7-1 and B7-2 on resting B cells showed that soluble gp39 up-regulated B7-1 and B7-2 expression on B cells. In addition, interleukin-4 and interferon-gamma up-regulated B7-2 expression on B cells. Taken together, these data demonstrate that the antigen-induced expression of gp39 is dependent on TCR-derived signals, yet independent of CD28/CTLA-4 co-stimulatory signals. Cognate interactions also resulted in the modest enhancement of B7-1 expression and a more profound expression of B7-2 which were completely or partially dependent on gp39-CD40 interactions.

Abatacept↗

PubMed1992

T helper cells.

B-cell proliferation and differentiation is controlled by T helper cells. Recent studies have determined that the expression of a novel, 39 kD, T-cell membrane protein is responsible for inducing T-cell-dependent B-cell activation. The receptor for this protein on the resting B cell is CD40. Once activated, B cells are induced to grow and differentiate by the elaboration of interleukin-4 and interleukin-5 from activated T cells. Together, T cell-B cell contact and soluble factors provide all the signals required for B-cell growth and differentiation.

Animals↗

PubMed1984

Increased expression of Ia antigens on resting B cells: an additional role for B-cell growth factor.

The present studies demonstrate that both T-cell-derived supernatants containing B-cell growth factor (BCGF or BSF) and a partially purified preparation of the B-cell growth factor (BSF-p1) induce an increase in the expression of IA and IE-encoded antigens on small resting B cells. This increase is detectable by 6-8 hr after initiation of culture and is relatively selective, since levels of surface immunoglobulin and H-2 antigens do not increase to the same extent. Although interferon-gamma induces increased expression of Ia antigens on macrophages and dividing neoplastic B cells, it does not induce an increase in the expression of Ia antigens on resting B cells. These results demonstrate that BSF-p1 may play two roles: (i) it acts on resting B cells to increase the levels of Ia antigen expression; and (ii) it sustains the growth of B cells that have been previously activated with mitogens, antigens, or anti-Ig.

Animals↗