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Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice.

Möröy, T; Grzeschiczek, A; Petzold, S; Hartmann, K U
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/11/1993 EN
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Transgenic mice expressing the Pim-1 kinase are predisposed to develop T-cell lymphomas with a long latency period of about 7-9 months. However, the exact functional basis of the oncogenic activity of Pim-1 remains obscure. C57BL/6 mice homozygous for the lpr mutation develop a well-described lymphoproliferative syndrome at about 26-30 weeks of age. This syndrome is characterized mainly by the accumulation of abnormal T cells in lymph nodes because of the lack of Fas receptor-induced apoptosis. We find that backcross of E mu-Pim-1 transgenics (mice with a transgene that carries the mouse Pim-1 gene under the transcriptional control of the immunoglobulin heavy chain gene enhancer E mu) into lpr/lpr mice results in strong acceleration of lymphoproliferation and dramatic enlargement of lymph nodes. In addition, we show here that cultured lymph node cells from E mu-Pim-1 lpr/lpr mice are rescued from rapid apoptosis that normally occurs in nontransgenic lpr cells in vitro. We also present evidence that CD4+/CD8+ double-positive thymocytes from lpr/lpr mice are sensitive to dexamethasone-induced apoptosis, although lpr/lpr mice lack the Fas receptor. In contrast, E mu-Pim-1 lpr/lpr animals show considerable protection from dexamethasone-induced apoptosis. These results show that Pim-1 can strongly accelerate lymphoproliferation through inhibition of apoptosis and thereby provide first insight into the functional basis for the oncogenic activity of Pim-1.

Tyrosine phosphorylation of a c-Src-like protein is increased in membranes of CD4- CD8- T lymphocytes from lpr/lpr mice.

Katagiri, T; Ting, J P; Dy, R; Prokop, C; Cohen, P; Earp, H S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1989 EN
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Mice homozygous for the autosomal recessive lpr gene have a disorder that results in autoimmunity and massive accumulation of T lymphocytes lacking CD4 and CD8 surface markers. These abnormal T cells exhibit constitutive tyrosine phosphorylation of a component of the CD3-T-cell receptor complex. We compared membrane tyrosine phosphorylation in lpr/lpr CD4- CD8- T cells and control T cells, lpr membranes exhibited a 7.3-fold increase (n = 16) in tyrosine phosphorylation of a 60-kilodalton protein. The increase was correlated with the Lpr but not the CD4- CD8- phenotype in that p60 phosphorylation was not increased in membranes from normal CD4- CD8- thymocytes. To identify the p60 in lpr cells, we examined the activity of several T-cell tyrosine-specific protein kinases. p56lck phosphorylation was only slightly increased in lpr membranes (2.2-fold; n = 16). Phorbol ester treatment of intact T cells before membrane isolation caused p56lck to migrate as pp60lck; however, pp60lck could be clearly distinguished from the pp60 in lpr cells by two-dimensional gel electrophoresis. The pp60 from lpr cells exhibited several isoforms at pH approximately 6.3 to 6.5. Although on two-dimensional gels pp60c-src had a pI (6.4 to 6.8) within a similar region...

Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations.

Thomas, T J; Gunnia, U B; Seibold, J R; Thomas, T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/10/1995 EN
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We previously reported that difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, exerted significant beneficial effects on the lifespan and disease expression of MRL-lpr/lpr mice, which spontaneously develop a lupus-like syndrome. Polyamine levels in splenic T-cells of MRL-lpr/lpr mice were significantly higher than those of Balb/c mice. In the present investigation, we examined the role of endogenous polyamines in transmembrane Ca2+ influx, generation of InsP3 and tyrosine phosphorylation of the p56lck protein in concanavalin A-stimulated splenic T-cells. Cytosolic free calcium concentrations ([Ca2+]i) in concanavalin A-stimulated T-cells of MRL-lpr/lpr and Balb/c mice were 250 +/- 25 and 450 +/- 42 nM respectively. Treatment of MRL-lpr/lpr mice with DFMO increased [Ca2+]i to 360 +/- 30 nM (P < 0.05). InsP3 levels of concanavalin A-stimulated MRL-lpr/lpr splenic T-cells were only 20% higher than those of unstimulated controls, whereas those of Balb/c T-cells were 90% higher. DFMO treatment increased InsP3 levels in concanavalin A-treated MRL-lpr/lpr T-cells to 67%. Western-blot analysis showed a 7-fold higher level of p56lck phosphorylation of MRL-lpr/lpr splenic T-cells than that of Balb/c mice. DFMO treatment reduced tyrosine phosphorylation of p56lck of MRL-lpr/lpr mice significantly (P < 0.001). Two-colour flow-cytometric analysis revealed no significant difference in the CD4+/CD8+ ratio in splenic T-cells of MRL-lpr/lpr mice after DFMO treatment. Polyamine levels in splenocytes were significantly reduced by DFMO treatment. These data show that DFMO treatment could alter signal-transduction pathways of splenic T-cells of MRL-lpr/lpr mice. Increased levels of polyamines in T-cells of untreated lpr mice contribute to defective signal-transduction pathways and the pathogenesis of lupus-like symptoms.

Different expression of T-cell receptor beta-chain variable region genes in lymph nodes of lpr mice with different alleles of the major histocompatibility complex.

Ohga, S; Yoshikai, Y; Kishihara, K; Matsuzaki, G; Ogimoto, M; Nomoto, K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1990 EN
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In order to search for a possible role of abnormally proliferating T cells in developing autoimmune disease in lpr mice, and to define the difference of the T cells among various lpr-congeneic mice with different clinicopathological findings, the T-cell receptor (TcR) V beta gene expression in the enlarged lymph nodes (LN) of C3H/HeJ-lpr/lpr (C3H-lpr), C57BL/6-lpr/lpr (B6-lpr) and MRL/Mp-lpr/lpr (MRL-lpr) mice was analysed. A RNA blot analysis using several V beta-specific probes showed that the V beta 3 gene, whose products are important for recognizing Mlsb/a, was used in B6-lpr and MRL-lpr with the Mlsb/b but not in C3H-lpr with the Mlsb/a. The V beta 5 gene, which is selectively related to I-E molecules, was predominantly used in B6-lpr(I-E-) but not in C3H-lpr(I-E+) nor MRL-lpr(I-E+). Similarly, the V12 gene was also expressed in B6-lpr but not in C3H-lpr. To compare in detail in V beta repertoire among lpr mice with different major histocompatibility complex (MHC) backgrounds, the V beta gene sequences in the cDNA libraries from LN cells of C3H-lpr were analysed, following the recent investigation of B6-lpr mice (Ohga et al., 1989). Eleven beta-chain cDNA out of 32 beta cDNA in B6-lpr and 24 beta-chain cDNA out of 55 beta cDNA in C3H-lpr were found to contain sequences with open reading frames that potentially encode functional TcR beta-chain. The frequencies of the messages in the cDNA libraries from these mice were consistent with the RNA blot analysis using V beta 3- and V beta 5-specific probes. It was notable that 36% of the functional beta-chain mRNA in B6-lpr and 50% of the beta mRNA in C3H-lpr expressed the V beta 8 gene family. When the TcR V beta gene expression was compared between the LN cells in C3H-lpr...

Reciprocal haematopoietic cell transfers between C57BL/6 mice differing at the lpr locus.

Montecino-Rodriguez, E M; Loor, F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1991 EN
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27.72%
Reciprocal transfers of spleen and bone marrow cell suspensions have been performed between mice of the C57BL/6 (B6) genetic background, differing at the lymphoproliferation (lpr) locus. These immune system chimaeras were followed for almost one year after sublethal irradiation and cell reconstitution. In addition to the survival of the chimaeras, the major lymphoid organs (bone marrow, spleen, thymus and lymph nodes) were examined for cell numbers, percentages of membrane immunoglobulin-positive cells and responses to mitogenic stimulations with concanavalin and lipopolysaccharide. The [lpr----lpr] chimaeras were similar to untreated lpr mice. The [wild----lpr] did not develop the lpr-induced syndrome and remained similar to [wild----wild] chimaeras. Therefore, B6 wild haematopoietic stem cells could rescue sublethally irradiated B6 lpr mice from the lpr-induced autoimmune pathology. The radioresistant lpr environment alone was not sufficient to induce the lpr syndrome. It may however be required for its development since [lpr----wild] chimaeras displayed a profound aplasia of their lymphoid organs, together with a normal cellularity of their bone marrow. In contrast to chimaeras constructed with MRL mice, the [lpr----wild] B6 chimaeras did not die following the lpr haematopoietic stem cell transfer. Therefore...

Partial expression of the lpr locus in the heterozygous state: presence of autoantibodies.

Jachez, B; Montecino-Rodriguez, E; Fonteneau, P; Loor, F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1988 EN
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27.75%
B6 mice heterozygous at the lpr locus (B6 +/lpr and B6 lpr/+) were compared with lpr homozygous mice (B6 lpr/lpr) and control mice (B6 +/+) for levels of serum immunoglobulin (Ig), presence of autoantibodies and rate of B-cell membrane immunoglobulin (mIg) capping. The total serum Ig levels in B6 +/lpr and B6 lpr/+ mice remained much below the high titres found in B6 lpr/lpr mice, and were close to the titres found in B6 +/+ mice. However, the presence of anti-single-stranded (ss) DNA antibodies and of anti-nuclear antibodies (ANA) was detected in most B6 +/lpr and B6 lpr/+ mice, although less frequently and in lower titres than in B6 lpr/lpr mice. The rate of mIg capping was higher in B6 +/lpr and B6 lpr/+ mice than in B6 +/+ mice, but the acceleration of the capping process remained inferior to the one found in B6 lpr/lpr mice. Therefore, the lpr locus is not totally recessive: some B-cell hyperactivity is expressed in the heterozygous state. This is in contrast with its lack of expression at the level of lympho-proliferation of the lpr-characteristic T-cell subset: none of the lpr heterozygous B6 mice displayed detectable lymphadenopathy.

Lack of transfer of lpr-type abnormalities (lymphoproliferation or lymphoid aplasia) in double congenic nude beige mice engrafted with lpr haematopoietic cells.

Tiberghien, F; Pflumio, F; Kuntz, L; Loor, F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1993 EN
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The aetiology of the autoimmune and lymphoproliferative syndrome caused by the murine lpr (lymphoproliferation) mutation was studied by the adoptive transfer methodology using non-irradiated athymic and natural killer (NK)-deficient C57BL/6 nude beige mice (B6 nubg) as recipients. The [lpr-->nubg] chimeras did not display the severe lymphoid organ aplasia shown by irradiated non-lpr recipients of lpr haematopoietic cells. However, nor did they either express the typical lpr phenotype features (hyperglobulinaemia, autoimmunity and lymphoid hyperplasia). Nevertheless, engraftment of lpr cells in the nubg recipients was shown by their much increased survival, the recovery of T-cell mitogen responsiveness in the spleen, and the presence of T-dependent immunoglobulin isotypes in their serum. The host of donor origin of serum immunoglobulin was studied by measuring IgG2a allotypes in the serum of [lpr-->nubg] chimeras made with different lgh-congenic mice. Interestingly, several months after grafting, the serum IgG2a was found to be mainly of lpr graft origin, suggesting that only lpr B cells could function in such chimeras. In conclusion, a lpr spleen cell graft reconstituted non-irradiated nubg recipients and induced neither a typical lpr syndrome nor a lpr-type graft-versus-host (GVH)-like disease. These features of the lpr syndrome are at variance with those of the phenotypically similar gld syndrome...

Attenuation of lpr-graft-versus-host disease (GVHD) in MRL/lpr spleen cell-injected SCID mice by in vivo treatment with anti-V beta 8.1,2 monoclonal antibody.

Hosaka, N; Nagata, N; Miyashima, S; Ikehara, S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1994 EN
Relevância na Pesquisa
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When MRL/lpr (H-2k) spleen cells were intraperitoneally injected into C.B-17-scid/scid (severe combined immunodeficient (SCID)) (H-2d) mice, the SCID (SCID-MRL/lpr) mice manifested a severe wasting syndrome with weight loss, splenic atrophy, and lymphoid cell infiltration in the liver and lung, as seen in lpr-GVHD. In contrast, MRL/+ spleen cell-injected SCID (SCID-MRL/+) mice did not show lpr-GVHD. The spleens of SCID-MRL/lpr mice showed progressive increases in donor CD4+ and CD8+ T cells from 4 to 12 weeks after injection and a decrease in B cells at 12 weeks. SCID-MRL/+ mice showed a stable engraftment of CD4+ and CD8+ T cells and a progressive increase in B cells. Analyses of T cell receptor (TCR) repertoires (V beta 6, V beta 8.1,2 and V beta 11) revealed that the V beta 8.1,2+ T cells were found more frequently in SCID-MRL/lpr mice than in SCID-MRL/+ mice. When SCID-MRL/lpr mice were treated with intraperitoneal injection of an anti-V beta 8.1,2 (KJ16) MoAb, V beta 8.1,2+ T cells were markedly depleted, and the severity of lpr-GVHD was attenuated at 4 and 8 weeks after treatment, in contrast to normal rat IgG-injected SCID-MRL/lpr mice. However, the KJ16 MoAb-treated SCID-MRL/lpr mice suffered from severe lpr-GVHD 12 weeks after treatment...

Expression and sequences of T cell receptor beta-chain variable genes in the enlarged lymph nodes of C57BL/6-lpr/lpr mice.

Ohga, S; Yoshikai, Y; Kishihara, K; Matsuzaki, G; Asano, T; Nomoto, K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1989 EN
Relevância na Pesquisa
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An autosomal recessive gene, lpr, is responsible for lymphoproliferation and autoimmunity of lpr-mice, in which background genes are also known to influence the development of autoimmune disease. To define the differences in abnormally proliferating T cells between C57BL/6-lpr/lpr and MRL/Mp-lpr/lpr mice, and to try and understand the influence of background in the differing expression of autoimmune disease in both strains, we analysed the sequences of T cell antigen receptor V beta genes expressed in the cells from the enlarged lymph nodes of C57BL/6-lpr/lpr mice. Eleven beta cDNAs out of the 38 C beta-specific cDNAs contained sequences with open reading frames from the beginning of the variable region to the expected termination codons at the end of the constant regions. Notably, 36% of the functional beta-chain mRNAs expressed V beta 8.3 genes, whereas V beta 8.1 and V beta 8.2 genes were not found. These results are consistent with a relatively lower frequency of the V beta 8.1 or V beta 8.2 expressing cells in the hypertrophic lymph nodes of C57BL/6-lpr/lpr mice, detected by KJ16-133 monoclonal antibody. Interestingly, other V beta genes expressed in these mice were completely distinct from those in MRL/Mp-lpr/lpr mice as described by Singer et al. (1986). The different distribution of V beta genes expressed in C57BL/6-lpr/lpr from that in MRL/Mp-lpr/lpr mice might be related to the differences in the genetic background and the expression of lpr gene-associated autoimmunity.

Unusual cell surface properties of the T lymphocyte population expanding in MRL/Mp-lpr/lpr mice.

Dumont, F; Habbersett, R G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1982 EN
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MRL/Mp-lpr/lpr (lpr/lpr) mice but not the congenic MRL/Mp-+/+ (+/+) mice, develop a generalized lymph node (LN) hypertrophy reflecting the expansion of a T-cell population that acts as an enhancing factor for autoimmunity. In order to characterize better this T-cell population, we investigated some of its surface properties in comparison with those of +/+ T cells. Electrophoretic measurements revealed that lpr/lpr T cells possess a lower electronegative surface charge than %/% T cells which indicates that the two cell types differ in the molecular composition of their plasmic membrane periphery. This notion was substantiated by the quantification of T- and B-cell markers and of lectin-binding sites on these cells using single- and two-colour flow cytofluorimetry. In agreement with recent observations by Lewis, Giorgi & Warner (1981) lpr/lpr T cells exhibited lower levels of Thy-1 and Lyt-1 antigens than +/+ T cells and were mostly devoid of Lyt-2 antigen. Although lpr/lpr lymph node (LN) cells displayed similar amounts of surface receptors for peanut agglutinin as +/+ LN cells, the expression of surface receptors for other lectins were either lower (Limulus polyphemus agglutinin, Maclura pomifera agglutinin, Concanavalin A) or higher (Helix pomatia agglutinin...

Defect in negative selection in lpr donor-derived T cells differentiating in non-lpr host thymus

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/01/1991 EN
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Transplantation of bone marrow cells of lpr/lpr mice into irradiated normal mice fails to develop massive lymphadenopathy or autoimmunity but causes severe graft-vs.-host-like syndrome. To elucidate an abnormality of lpr/lpr bone marrow-derived T cells, we transplanted bone marrow cells of Mlsb lpr/lpr mice into H-2-compatible Mlsa non-lpr mice. Although lpr/lpr T cell precursors repopulated the host thymus as well as +/+ cells, a proportion of CD4+CD8+ cells decreased, and that of both CD4- and CD8- single-positive cells increased compared with those of +/+ recipients. Notably, in MRL/lpr----AKR and C3H/lpr----AKR chimeras, CD4 single-positive thymocytes contained an increased number of V beta 6+ cells in spite of potentially deleting alleles of Mlsa, whereas V beta 6+ mature T cells were deleted in the MRL/+ ----AKR and C3H/+ ----AKR chimeras. There was no difference between MRL/+ ----AKR and MRL/lpr----AKR chimeras in their proportion of V beta 3+ cells because both host and donor strain lack the deleting alleles. Interleukin 2 receptor expression of mature T cells, in the thymus and lymph node, was obviously higher in the MRL/lpr----AKR chimeras, in particular in the "forbidden" V beta 6+ subset. Moreover, lpr donor- derived peripheral T cells showed vigorous anti-CD3 response. These results indicate that lpr-derived T cells escape not only tolerance- related clonal deletion but also some induction of unresponsiveness in the non-lpr thymus.

Defective maintenance of T cell tolerance to a superantigen in MRL- lpr/lpr mice

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/10/1992 EN
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In normal mice neonatal injection of staphylococcal enterotoxin B (SEB) induces tolerance in T cells that express reactive T cell receptor (TCR) V beta regions. To determine if a T cell neonatal defect was present in MRL-lpr/lpr mice, 20 micrograms of SEB was injected intraperitoneally every other day into V beta 8.2 TCR transgenic and nontransgenic MRL(-)+/+ and MRL-lpr/lpr mice from birth to 2 wk of age. At 2 wk of age, V beta 8+ T cells were depleted, and SEB reactivity was lost, in spleen, lymph node, and thymus. These effects were equivalent in +/+ and lpr/lpr SEB-tolerized mice. However, MRL-lpr/lpr mice failed to maintain neonatal tolerance. By 4 wk of age, there was a dramatic increase in T cells expressing V beta 8.2 in the peripheral lymph nodes of MRL-lpr/lpr mice but not MRL(-)+/+ mice. In vitro stimulation with SEB or TCR crosslinking revealed a total loss of neonatal tolerance 2 wk after cessation of SEB treatment in lpr/lpr mice, but not +/+ mice. The time-course of recovery of V beta 8+ T cells and reactivity to SEB and TCR crosslinking in the thymus of MRL-lpr/lpr mice was similar to that in the lymph node. Thymectomy at 2 wk of age eliminated tolerance loss in lymph nodes of MRL-lpr/lpr mice at 4 wk of age, indicating that loss of peripheral tolerance was due to the emigration of untolerized T cells from the thymus. Challenge of neonatally tolerized MRL-lpr/lpr mice with SEB (100 micrograms...

Influence of thymic genotype on the systemic lupus erythematosus-like disease and T cell proliferation of MRL/Mp-lpr/lpr mice

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/06/1981 EN
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27.73%
In young adulthood, MRL/Mp-lpr/lpr mice develop severe systemic lupus erythematosus (SLE)-like syndrome associated with massive T cell proliferation. The congenic MRL/Mp- mice lack the lpr gene and develop chronic SLE late in life. We have exchanged thymic transplants between these substrains so as to determine the role of the thymus in the development of early, severe SLE and of lymphoproliferation. The median survival times of unmanipulated lpr/lpr and mice were 160 and 510 d, respectively. The lpr/lpr and mice thymectomized when newborn and transplanted at 1 mo with the opposite type of thymus retained the diseases phenotype of their unmanipulated counterparts with 50% mortality at 186 and 498 d, respectively. In contrast, lpr/lpr mice thymectomized when newborn but not transplanted with thymus did not develop lymphoid hyperplasia and glomerulonephritis, and 100% of them were alive at 390 d. Serologically, the thymectomized but untransplanted lpr/lpr mice had significantly reduced levels of autoantibodies, whereas thymectomized and transplanted mice of either substrain were similar to unmanipulated controls. The results indicate that: (a) a thymus is essential for expression of lymphoproliferation and early SLE-like disease in the lpr/lpr phenotype; (b) the lpr/lpr disease is not a result of a unique hormonal or microenvironmental defect(s) of the thymus of this substrain because the genotype of the thymus is irrelevant for the development of T cell proliferation and early SLE; (c) differentiation of stem cells under the hormonal or microenvironmental influences of a thymus that possesses the lpr genotype does not lead to abnormal T cell differentiation or early autoimmunity; and (d) the lpr/lpr disease cannot be caused exclusively by an intrinsic B cell defect or environmental stimuli that cause B cell polyclonal activation.

A new allele of the lpr locus, lprcg, that complements the gld gene in induction of lymphadenopathy in the mouse

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/02/1990 EN
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27.71%
Several mice with generalized lymphadenopathy were found in the CBA/KlJms (CBA) colony maintained at our institute. A new mutant strain of mice that develop massive lymphoid hyperplasia at 100% incidence within 5 mo after birth was established by crossing these diseased mice. Genetic studies on lymphadenopathy were conducted in F1, F2, and backcross populations from crosses between mutant CBA (CBA-m) and various inbred strains of mice. The results supported the control of lymphadenopathy by a single autosomal recessive gene. Since C3H/He- gld/gld (C3H-gld), MRL/MpJ-lpr/lpr (MRL-lpr), and C3H/HeJ-lpr/lpr (C3H- lpr) mice develop the same type of lymphoid hyperplasia, allelism of the mutant gene with gld or lpr was tested by investigating lymphadenopathy in F1 and backcross populations from crosses between CBA-m and C3H-gld, MRL-lpr, or C3H-lpr mice. The gene was confirmed to be allelic with lpr but not with gld. Interestingly, however, the mutant gene interacted with gld to induce less severe lymphadenopathy. Thus, the mutant gene was named lprcg, an lpr gene complementing gld in induction of lymphoproliferation. The genetic conclusion was supported by the same profile of surface markers of lymphoid cells with gld/gld, lpr/lpr, lprcg/lprcg...

Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/11/1990 EN
Relevância na Pesquisa
27.71%
Homozygosity for either of the lymphoproliferation (lpr) or generalized lymphoproliferative disease (gld) mutations of mice causes the development of systemic lupus erythematosus-like autoimmune syndromes that are characterized by severe lymphadenopathy and highly elevated serum immunoglobulin levels. Although the mutations are nonallelic, analysis of homozygous lpr/lpr and gld/gld mice on the same strain background has indicated that the pathology and severity of the autoimmune syndromes induced by these mutations are indistinguishable. To explain this, it has previously been suggested that lpr and gld may represent mutations in molecules involved in sequential steps of an intracellular metabolic pathway of T cells. We have now investigated the behavior of both lpr and gld in a variety of bone marrow chimeras and have found that functional differences between lpr and gld become apparent after bone marrow transfer. Transfer of lpr/lpr bone marrow to irradiated congenic +/+ recipients caused the development of a graft- vs.-host-like lymphoid wasting syndrome, whereas transfer of gld/gld bone marrow to +/+ recipients resulted in development of a gld-like autoimmune syndrome. Additionally, gld/gld hosts behaved like +/+ hosts irrespective of the genotype of the donor bone marrow...

Transgenic rearranged T cell receptor gene inhibits lymphadenopathy and accumulation of CD4-CD8-B220+ T cells in lpr/lpr mice

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/12/1990 EN
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27.77%
The lpr gene in homozygous form induces development of CD4-CD8-B220+ T cells and lymphadenopathy in MRL and C57BL/6 mice. Although the propensity for excessive production of T cells is related to an intrinsic T cell defect, a thymus is also required because neonatal thymectomy eliminates lymphadenopathy. Recent evidence suggests that excessive production and release of autoreactive T cells from the thymus of lpr/lpr mice might lead to downregulation of CD4 and CD8 as a "fail safe" tolerance mechanism that occurs during late thymic or post- thymic development. To test this hypothesis, T cell receptor (TCR) transgenic mice that produce large numbers of immature thymocytes recognizing the H-2Db and male H-Y antigens were backcrossed with C57BL/6-lpr/lpr mice and MRL-lpr/lpr mice. It was predicted that Db male lpr/lpr mice would produce large numbers of autoreactive T cells during early thymic development that would lead to an accelerated lymphoproliferative disease. In contrast, Db female lpr/lpr mice would produce large numbers of Db H-Y-reactive T cells, but might not develop lymphadenopathy because the male H-Y antigen would not be present. Unexpectedly, there was complete elimination of lymphadenopathy in both male and female TCR transgenic lpr/lpr mice. The elimination of lymphadenopathy was not due to a failure of thymic maturation since the thymus of H-2Db female lpr/lpr mice contained nearly normal numbers of mature thymocytes. Elimination of lymphadenopathy was also not due to a lack of autoreactive T cells in the peripheral lymph nodes (LN) since there was an increased syngeneic mixed lymphocyte proliferative response of LNT cells from transgenic lpr/lpr compared with +/+ mice in vitro. Hypergammaglobulinemia and autoantibody production in the transgenic lpr/lpr was present at levels comparable with or higher than control nontransgenic lpr/lpr mice...

The lpr gene causes an intrinsic T cell abnormality that is required for hyperproliferation

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/03/1988 EN
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The lpr gene induces marked lymphoproliferation characterized by the massive accumulation of T cells of an unusual phenotype and concomitant autoimmune disease. To clarify the mechanism of the lpr effect, bone marrow cells from B6-lpr/lpr (Ly-1.2) and B6-+/+ (Ly-1.1) mice were transferred into lethally irradiated B6-lpr/lpr mice. As has been previously reported, recipients of the B6-lpr/lpr bone marrow showed the typical lpr phenotype with marked lymphadenopathy, splenomegaly and increased levels of autoantibodies; while the recipients of B6-+/+ bone marrow had normal sized lymph nodes and spleen and no autoantibodies. A third group of mice received an equal mixture of bone marrow cells from the B6-lpr/lpr and B6-+/+ donors. These mice showed both lymphadenopathy and autoantibody production comparable to that of recipients of the B6-lpr/lpr marrow alone. Immunofluorocytometric analysis of the lymphoid populations in these mixed bone marrow recipients established that the T cells from the lpr/lpr and +/+ donors were equivalently represented in the peripheral blood and thymus. In striking contrast, the T cells that accumulated in abnormally large numbers in the lymph nodes were almost entirely from the lpr donor. Their surface phenotype was Thy-1+(dull)...

The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L- arginine

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/02/1994 EN
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MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL- lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However...

Clinical and Serologic Manifestations of Autoimmune Disease in MRL-lpr/lpr Mice Lacking Nitric Oxide Synthase Type 2

Gilkeson, Gary S.; Mudgett, John S.; Seldin, Michael F.; Ruiz, Phil; Alexander, Audrey A.; Misukonis, Mary A.; Pisetsky, David S.; Weinberg, J. Brice
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 04/08/1997 EN
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Nitric oxide (NO) is an important mediator of the inflammatory response. MRL–lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl–arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL–lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL–lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL–lpr/lpr mice to the N4 generation. MRL–lpr/lpr littermates homozygous for disrupted NOS2 (−/−), heterozygous for disrupted NOS2 (+/−), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (−/−) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/−) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (−/−) animals, whereas that of (+/+) was high and (+/−) intermediate. The (−/−) mice developed glomerular and synovial pathology similar to that of the (+/−) and (+/+) mice. However...

An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/06/1991 EN
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Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented...