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Biomedical subjects

A W Harris

Publications and source records attributed to A W Harris.

At least 73 records · Page 4Linked to original sources
PubMed1994

Bcl-2 expression promotes B- but not T-lymphoid development in scid mice.

Expression of antigen receptors is vital for the development of B and T lymphocytes. In mice with the scid mutation, which are unable to make productive rearrangements of their immunoglobulin and T-cell receptor (TCR) genes, lymphopoiesis aborts at an early stage. The death of the immature lymphocytes by apoptosis is postulated to result from a failure to receive a survival signal induced by receptor engagement. Consistent with this hypothesis, introduction of immunoglobulin or TCR transgenes into scid mice promoted an increase in B- or T-lymphoid cells, respectively. As the protein encoded by the bcl-2 gene can inhibit cell death, we tested whether lymphopoiesis could be rescued in scid mice by crossing in a bcl-2 transgene. Strikingly, the bcl-2/scid mice accumulated almost normal numbers of B-lymphoid cells which lacked surface immunoglobulin but expressed markers of maturity. T-cell development remained blocked. Introducing a TCR transgene enabled bcl-2/scid mice to develop normal numbers of CD4+8+ thymocytes even in the absence of immunological selection, suggesting that T cells become competent to respond to bcl-2 protein only after the TCR complex is displayed at the cell surface.

Animals↗
PubMed1994

Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene.

To explore the role of bcl-2 in T-cell development, a bcl-2 transgene was introduced into mice expressing a T-cell receptor (TCR) transgene encoding reactivity for the mouse male antigen HY presented by the H-2Db class I antigen of the major histocompatibility complex (MHC). Normal thymic development is contingent on the ability of immature thymocytes to interact with self-MHC molecules presented by thymic stroma (positive selection). Thus, thymocyte numbers are low in female anti-HY TCR transgenic mice with a nonselecting (H-2Dd) background. Expression of bcl-2 inhibited the death of nonselectable thymocytes since, strikingly, female H-2Dd bcl-2/TCR transgenic mice developed normal numbers of CD4+CD8+ thymocytes, although these did not mature further into functional T cells. Hence, TCR-MHC interaction may induce positive selection through two signals, one which saves cells from death by increasing Bcl-2 synthesis and another which promotes maturation. Male H-2Db anti-HY TCR transgenic mice normally have a very small thymus, due to deletion of the self-reactive T cells. Expression of bcl-2 reduced the efficiency of deletion, since bcl-2/TCR transgenic male mice accumulated 4- to 6-fold more thymocytes than did TCR transgenic male littermates. Anti-HY TCR-expressing cells were also more numerous in the peripheral lymphoid tissues, but these cells expressed abnormally low levels of CD8 co-receptor and were not responsive to the HY antigen. Thus, although bcl-2 expression hampers the deletion of immature self-reactive cells in the thymus, self-tolerance is maintained.

Animals↗
PubMed1994

B-lymphoid to granulocytic switch during hematopoiesis in a transgenic mouse strain.

B-lymphoid and myeloid development are markedly perturbed in a unique transgenic mouse strain, max 41. Pro-B, pre-B, and B lymphocytes were severely reduced but granulocytes were greatly elevated. This phenotype could be adoptively transferred with bone marrow cells. It was not alleviated by bcl-2 or myc transgenes that promote lymphocyte survival or proliferation. Bitransgenic myc/max 41 mice developed pre-B cell lymphoma. An accompanying massive granulocytosis unexpectedly proved to be clonally derived from the pre-B lymphoma cells. These observations suggest that B lymphopoiesis in max 41 mice has been diverted to granulocyte production. Since neither cell type expressed the transgene, this novel lymphomyeloid deviation probably reflects insertional alteration of a hematopoietic regulatory gene.

Animals↗
PubMed1994

The coronally positioned pedicle graft with inlaid margins: a predictable method of obtaining root coverage of shallow defects.

There are several techniques that will predictably cover exposed root surfaces; however, most techniques are generally used to treat larger recession areas or sites with inadequate keratinized tissue. The purpose of this study is to evaluate the use of the coronally positioned pedicle graft with inlaid margins in the treatment of shallow recession areas. Utilizing the described technique, 20 isolated Class I defects were treated. Complete root coverage was obtained 95% of the time; the mean root coverage was 98.8%. The procedure resulted in a decrease in sensitivity, the final color and tissue contours of the grafts were excellent, and all patients were satisfied with the results. The coronally positioned pedicle graft with inlaid margins is a simple and predictable method to cover exposed root surfaces in shallow recession areas.

Adult↗
PubMed1993

Moloney virus induction of T-cell lymphomas in a plasmacytomagenic strain of E mu-v-abl transgenic mice.

Although the v-abl gene can provoke several types of lymphoid neoplasm, mice of a transgenic strain (E mu-v-abl 40) in which lymphocytes are targeted for expression of v-abl by a linked immunoglobulin enhancer (E mu) spontaneously develop only plasmacytomas. To determine whether other lymphocytes of this strain were susceptible to transformation, and to identify genes that can collaborate with v-abl in tumorigenesis, E mu-v-abl 40 mice were subjected to insertional mutagenesis by neonatal infection with Moloney murine leukemia virus. Tumorigenesis was accelerated moderately, but nearly all the tumors were T lymphomas. The altered tumor type may reflect both the T-cell tropism of Moloney virus and the higher level of E mu-v-abl 40 expression found in T lymphocytes than in B lymphocytes. Insertion near the c-myc, N-myc or pim-I gene was observed in 42% of the induced tumors, indicating that each of these genes may collaborate with v-abl in lymphomagenesis. Most of the accelerated tumors had a surprisingly low level of transgene expression. Thus, high expression of v-abl may not be required for Moloney-induced T lymphomagenesis.

Animals↗
PubMed1993

CD4+8- and CD4-8+ mature thymocytes require different post-selection processing for final development.

Two primary types of TCR-alpha/beta+ T cells are found in the peripheral lymphoid system; CD4+8- T cells, with MHC-class II restricted TCR, and CD4-8+ T cells, which are MHC-class I restricted. Both lineages develop in the thymus from a series of common precursors. However, the precise stage at which they diverge, and the combination of factors that regulates such divergence, are not well defined. The up-regulation of CD3/TCR to high mature levels is thought to be an early event associated with positive selection for self-MHC recognition. Using purified cells from bcl-2 transgenic mice in order to overcome the limitations imposed by cell death on normal thymocytes, we find that a minor subset of CD4+8+ thymocytes expressing high levels of CD3/TCR gives rise to both CD4+8- and CD4-8+ mature cells upon intrathymic transplantation, but only to CD4-8+ in culture. Thus, in addition to demonstrating the dual lineage potential of this subset, these findings show that additional post-selection processing events are required for the production of mature thymocytes, and that CD4+8- and CD4-8+ subsets differ in the types of processing required.

Animals↗
PubMed1993

Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death.

In transgenic mice, self-reactive B lymphocytes are eliminated if they encounter membrane-bound self antigens during their development within the bone marrow. We show here that two separate and sequential events, arrested development and cell death, bring about B cell elimination. Developmental arrest is an early outcome of antigen binding in immature B cells, blocks acquisition of adhesion molecules and receptors important for B cell migration and activation, and is rapidly reversible by removal of antigen. Death of the arrested B cells occurs within 1 to 3 days and can be delayed by expression of a bcl-2 transgene, which results in escape of large numbers of self-reactive B cells from the bone marrow but fails to override the developmental arrest. These findings define a novel pathway for B cell elimination, involving an initial stage vulnerable to breakdown in autoimmune disease.

Animals↗
PubMed1993

Is clubbing a feature of the anti-phospholipid antibody syndrome?

A patient with the anti-phospholipid antibody syndrome and digital clubbing is described. No recognized cause for the clubbing was found. It is suggested that platelet aggregation and microthrombi formation as a result of anti-phospholipid antibody may be involved in the pathogenesis of the digital clubbing. This may be a new feature of the anti-phospholipid antibody.

Antiphospholipid Syndrome↗
PubMed1993

bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis.

The bmi-1 gene was discovered as a frequent target of Moloney virus insertion in virally accelerated B-lymphoid tumors of E mu-myc transgenic mice and hence is thought to collaborate with the myc gene in lymphomagenesis, but its oncogenic potential has not previously been tested directly. To determine whether bmi-1 overexpression can contribute to hematopoietic neoplasia in vivo, strains of transgenic mice were generated in which bmi-1 expression was directed to the lymphoid compartment by a coupled immunoglobulin heavy chain enhancer (E mu). Although the E mu-bmi-1 transgene was expressed in both B and T cells, lymphoid development was not perturbed. Nevertheless, 14% of the mice in the strain with highest expression have developed lymphoma. Unexpectedly, most tumors were of the T-cell lineage, although one case of B lymphoma was observed. Furthermore, cross breeding E mu-bmi-1 and E mu-myc mice established that the bmi-1 transgene markedly accelerated the onset of pre-B and B lymphomas. These results demonstrate directly that bmi-1 can contribute to lymphomagenesis in the T and B cell lineages and collaborate with the myc gene in tumor development.

Animals↗
PubMed1993

E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells.

To assess the lymphoid tumorigenic potential of bcl-2, mice of five independent strains expressing a bcl-2 transgene in B and/or T cells were monitored for disease up to 12 months of age. Lymphoma prevalence was minimal in the T lineage but significant, although low (3-15%), in the B lineage. The principal types of tumors were plasmacytomas secreting immunoglobulin and novel lymphomas that expressed markers such as Sca-1, CD4, Thy-1, CD34 and CD45(B220), consistent with an origin very early in B-lymphoid development. Rearrangement of the c-myc gene was common in the plasmacytomas, implying a synergistic role for myc and bcl-2 in their etiology, but was not detected in the lymphomas.

Animals↗
PubMed1992

Retroviral infection accelerates T lymphomagenesis in E mu-N-ras transgenic mice by activating c-myc or N-myc.

Transgenic mice bearing a mutant, activated N-ras oncogene directed to express within hematopoietic cells by an immunoglobulin enhancer (E mu) sporadically develop T-cell lymphomas and non-lymphoid tumors that may be of macrophage origin. To identify genes that can collaborate with N-ras in hematopoietic neoplasia, Moloney murine leukemia virus was used as an insertional mutagen. Infection of newborn E mu-N-ras mice with the virus greatly accelerated tumorigenesis, and nearly all the tumors proved to be T-cell lymphomas. Their variable surface phenotype (CD4+CD8-, CD4+CD8+ and CD4-CD8-) suggested that cells at several stages of T-cell development were susceptible to tumorigenesis. Southern blot analysis revealed that 68% of the tumors bore a proviral insert 5' to the c-myc gene, while 13% had an insert within the 3' untranslated region of the N-myc gene. Insertion was associated with elevated expression of these genes. Hence, activation of a myc gene appears to be the dominant pathway to tumorigenesis by insertional mutagenesis in lymphoid cells expressing a mutant ras gene. However, since many of the tumors were not transplantable, even the partnership of myc and ras may not suffice for full lymphoid malignancy.

Animals↗
PubMed1991

bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.

Early death is the fate of most developing T lymphocytes. Because bcl-2 can promote cell survival, we tested its impact in mice expressing an E mu-bcl-2 transgene within the T lymphoid compartment. The T cells showed remarkably sustained viability and some spontaneous differentiation in vitro. They also resisted killing by lymphotoxic agents. Although total T cell numbers and the rate of thymic involution were unaltered, the response to immunization was enhanced, consistent with reduced death of activated T cells. No T cells reactive with self-superantigens appeared in the lymph nodes, but an excess was found in the thymus. These observations, together with previous findings on B cells, suggest that modulated bcl-2 expression is a determinant of life and death in normal lymphocytes.

Animals↗
PubMed1991

Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease.

The biological functions of the BCL2 gene were investigated in transgenic mice harboring human BCL2 cDNA under the control of an immunoglobulin heavy chain enhancer (E mu). Mice of a representative transgenic strain, E mu-bcl-2-22, had a great excess of B lymphocytes, immunoglobulin-secreting cells, and serum immunoglobulins, attributable to increased longevity of B-lineage cells. Pre-B and plasma cells as well as B cells exhibited prolonged survival in culture. Immunized animals produced an amplified and protracted antibody response. Within the first year of life, most mice spontaneously produced antibodies to nuclear antigens, and 60% developed kidney disease, diagnosed as immune complex glomerulonephritis. Thus E mu-bcl-2-22 mice constitute a transgenic model for a systemic autoimmune disease resembling the human disorder systemic lupus erythematosus.

Animals↗
PubMed1990

Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2.

The putative oncogene bcl-2 is juxtaposed to the immunoglobulin heavy chain (Igh) locus by the t(14;18) chromosomal translocation typical of human follicular B-cell lymphomas. The bcl-2 gene product is not altered by the translocation, but its expression is deregulated, presumably by the Igh enhancer E mu. Constitutive bcl-2 expression seems to augment cell survival, as infection with a bcl-2 retrovirus enables certain growth factor-dependent mouse cell lines to maintain viability when deprived of factor. Furthermore, high levels of the bcl-2 product can protect human B and T lymphoblasts under stress and thereby confer a growth advantage. Mice expressing a bcl-2 transgene controlled by the Igh enhancer accumulate small non-cycling B cells which survive unusually well in vitro but do not show a propensity for spontaneous tumorigenesis. In contrast, an analogous myc transgene, designed to mimic the myc-Igh translocation product typical of Burkitt's lymphoma and rodent plasmacytoma, promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells. Previous experiments have suggested that bcl-2 can cooperate with deregulated myc to improve in vitro growth of pre-B and B cells. Here we describe a marked synergy between bcl-2 and myc in doubly transgenic mice. E mu-bcl-2/myc mice show hyperproliferation of pre-B and B cells and develop tumours much faster than E mu-myc mice. Suprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.

Animals↗
PubMed1990

An E mu-v-abl transgene elicits plasmacytomas in concert with an activated myc gene.

To clarify how the v-abl oncogene of Abelson murine leukemia virus contributes to lymphoid tumorigenesis, we introduced the gene linked to an immunoglobulin heavy chain enhancer (E mu) into the mouse germline. Although lymphoid development was not detectably affected in young E mu-v-abl mice, three transgenic lines shared a high predisposition to develop clonal plasmacytomas that secreted IgA or IgG. The unexpected absence of pre-B lymphomas suggests that Abelson virus generates such tumors by infecting an early lymphoid progenitor cell that has not yet activated the heavy chain enhancer. Most plasmacytomas bore a rearranged c-myc gene, apparently as a result of spontaneous translocation to the Igh locus. Moreover, progeny of a cross with analogous E mu-myc mice rapidly developed oligoclonal plasmacytomas. Thus, the collusion of v-abl with c-myc is stage specific, efficiently transforming plasma cells but not pre-B cells or B cells.

Abelson murine leukemia virus↗