Biomedical subjects

T Abo

Publications and source records attributed to T Abo.

At least 55 records · Page 3Linked to original sources

PubMed2000

Anti-CD2 monoclonal antibodies prevent the induction of experimental autoimmune myocarditis.

We investigated the effect of a monoclonal antibody against CD2 molecules (OX34) in preventing the induction of experimental autoimmune myocarditis (EAM) induced by immunizing Lewis rats with cardiac myosin. Administration of OX34 before immunization, on Days -6, -4, -2 and 0, completely prevented EAM. On the other hand, treatment with OX34 just before the appearance of myocardial lesions, on Days 9, 11, 13 and 15, had only a partial effect in preventing the disease. Flow cytometric analysis of lymph node cells showed that CD3+ T cells were immediately depleted with the administration of OX34 but had largely recovered on Day 21. Lymph node cells in OX34-treated rats had no proliferative responses to cardiac myosin-rod, but the proliferation was restored when recombinant IL-2 was added. Ultimate production of the anti-myosin antibody was not inhibited by the treatment with OX34. These results suggest that the prevention of EAM by administering the anti-CD2 monoclonal antibody OX34 resulted from T cell depletion during the induction phase, and might in addition result from T cell anergy of Th1, but not Th2 cells.

Animals↗

PubMed2000

[Infection and regulation of leukocytes by autonomic nervous system].

The distribution of leukocyte pattern (i.e., the granulocyte to lymphocyte ratio) is changed by microbial infections. We found that the autonomic nervous system is also intimately associated with the inflammatory response. Even in the absence of such infections, the distribution of leukocyte pattern is changed by stimulation of the autonomic nervous system itself. When these changes become significant, people are susceptible to diseases such as purulent inflammation or allergic inflammation.

Autonomic Nervous System↗

PubMed1999

Identification of (CAG)(n) and (CGG)(n) repeat-binding proteins, CAGERs expressed in mature neurons of the mouse brain.

The trinucleotide repeats (CAG)(n) and (CGG)(n) have been shown to be expanded in responsible genes of several human hereditary neurological disorders. In studies of mice, we previously identified two homologous single-stranded (ss)(CAG) and ss(CGG) repeat-binding proteins, CAGER-1 (44 kDa) and CAGER-2 (40 kDa) (CAG-element-recognizing proteins). The specific binding activities of these proteins were predominantly detected in the mouse brain. We have isolated the cDNAs encoding CAGER-1 and CAGER-2 and found that they were identical to previously reported cDNAs for Puralpha and Purbeta, respectively. Puralpha of 28 kDa was previously identified as a replication-origin-binding protein that is ubiquitously expressed in proliferating cells. We show that the transcripts of CAGERs increase after birth and are detected at high levels in the adult mouse brain but at very low or virtually undetectable levels in other mouse tissues. Biochemical properties and molecular weights are different between CAGERs and Puralpha/beta. Immunostaining with specific antibodies against CAGERs indicates that CAGERs in the mouse brain reside in nonproliferating neurons but not in proliferating glia. We conclude that CAGERs and Puralpha/beta are unrelated proteins, and CAGERs are neuronal single-stranded sequence-binding proteins in the mouse brain. Misassignment of cDNAs is described.

Age Factors↗

PubMed1999

Mechanisms underlying immunologic states during pregnancy: possible association of the sympathetic nervous system.

NK and extrathymic T cells are abundant in the decidua of the pregnant uterus. To determine how this unique pattern is induced, overall populations of leukocytes were examined in the blood and other tissues in pregnant women. Time-kinetic studies showed that a basal change of leukocytes during pregnancy was granulocytosis and lymphocytopenia in the blood. This change might be due to sympathetic nerve activation during pregnancy, because the administration of catecholamine is known to activate myelopoiesis in the bone marrow. In addition to the numerical change, the functional activation of NK and extrathymic T cells also seemed to be present. This might be due to NK cells and extrathymic T cells (as well as granulocytes), which carry a high density of surface adrenergic receptors. Such functional activation of NK and extrathymic T cells was more prominent in the blood and urine in patients with preeclampsia and hyperemesis gravidarum than in normal pregnant women. The present results suggest that the activation of granulocytes, NK cells, and extrathymic T cells is essential for the maintenance of pregnancy but that overactivation thereof may be responsible for the onset of pregnancy disorders.

Adult↗

PubMed1999

CD4+ and/or gammadelta+ T cells in the liver spontaneously produce IL-4 in vitro during the early phase of Leishmania major infection in susceptible BALB/c mice.

Numerous studies on the cytokine production profile in Leishmania major infected susceptible and resistant mice have been carried out to elucidate the mechanisms of healing or non-healing of this infection. However, many methods may have failed to detect the actual cytokine production in the inflammatory foci. To overcome this problems, the ELISPOT assay was used to examine the spontaneous production of IL-4 and IFN-gamma in vitro by mononuclear cells from the spleen, lymph nodes and liver in L. major-infected susceptible BALB/c and resistant C57BL/6 mice. None of these mononuclear cells spontaneously produced IFN-gamma in either mouse strains in vitro in the absence of the corresponding antigen(s). However, liver mononuclear cells from infected BALB/c mice spontaneously produced IL-4 in vitro in as early as 2 weeks after the infection, but this was not observed in C57BL/6 mice. The IL-4 producing liver lymphocytes consisted of CD4+ and/or gammadelta+ T cells and uncharacterized cells. These results suggest that liver lymphocytes play some role in the establishment of Th2 prevalence in susceptible BALB/c mice, based on the importance of IL.4 production in the early phase of L. major infection in establishing Th2 dominance in this parasite susceptible mouse.

Animals↗

PubMed1999

Administration of glucocorticoids markedly increases the numbers of granulocytes and extrathymic T cells in the bone marrow.

Glucocorticoids, steroid hormones, are widely used as an anti-inflammatory drug. However, clinicians have sometimes encountered adverse drug reactions such as ulcers and tissue damage. In this study, we investigated how such adverse reactions of glucocorticoids are evoked, using an experimental mice model. When hydrocortisone (0.5 or 1.0 mg/day/mouse) was administered daily for 2 weeks, severe leukocytopenia was induced in all immune system organs. However, granulocytes (Gr-1(+)Mac-1(+)) were increased in number in the bone marrow and peripheral blood. This seemed to be due to an elevated level of myelopoiesis in the bone marrow. As well as increasing in number, granulocytes were functionally activated as estimated by the Ca2+ influx and superoxide production. The proportion of primordial T cells (CD3(int)IL-2Rbeta+) in the thymus and the number of primordial T cells in the bone marrow also increased. Mice administered hydrocortisone became susceptible to stress. Thus, these mice showed gastric ulcers when they were exposed to restraint stress for 12 h. These results suggest that activated granulocytes and primordial T cells might provide a mechanism involved in steroid ulcers and tissue damage, possibly through the superoxide production of granulocytes and the autoreactivity of primordial T cells.

Animals↗

PubMed1999

Expansion of extrathymic T cells as well as granulocytes in the liver and other organs of granulocyte-colony stimulating factor transgenic mice: why they lost the ability of hybrid resistance.

When we attempted to characterize the immunological state in G-CSF transgenic mice, a large number of not only granulocytes but also lymphoid cells expanded in various immune organs. Such lymphoid cells were present at unusual sites of these organs, e.g., the parenchymal space in the liver. We then determined the phenotype of these lymphoid cells by immunofluorescence tests. It was demonstrated that CD3intIL-2Rbeta+ cells (i.e., extrathymic T cells), including the NK1.1+ subset of CD3int cells (i.e., NKT cells), increased in the liver and all other tested organs. These T cells as well as NK cells mediated NK and NK-like cytotoxicity, especially at youth. However, they were not able to mediate such cytotoxicity in the presence of granulocytes. This result might be associated with deficiency in the hybrid resistance previously ascribed to these mice. In other words, G-CSF transgenic mice had a large number of extrathymic T cells (including NKT cells) and NK cells that mediate hybrid resistance, but their function was suppressed by activated granulocytes. Indeed, these granulocytes showed an elevated level of Ca2+ influx upon stimulation. The present results suggest that, in parallel with overactivation of granulocytes, extrathymic T cells and NK cells are concomitantly activated in number but that their function is suppressed in G-CSF transgenic mice.

Age Factors↗

PubMed1999

Protective effect of NK1.1(+) T cells as well as NK cells against intraperitoneal tumors in mice.

Peritoneal resident cells of mice normally contain small populations of NK cells and NK1.1(+) alphabetaT cells. These populations increased after either 3LL or EL4 tumor inoculations into the peritoneal cavity. In vivo depletion of NK cell alone by anti-asialo GM1 (ASGM1) Ab significantly decreased survival time of tumor-injected mice, while depletion of both NK cells and NK1.1(+) T cells by anti-NK 1.1 Ab greatly shortened mouse survival time. NK1. 1(+) T cells in peritoneal cavity consist of a larger proportion of double-negative T cells and smaller populations of CD4(+) T cells and Vbeta8(+) T cells compared with liver NK1.1(+) T cells and normally lack Vbeta2(+) T cells. Tumor inoculation induced rapid IL-12 and IFN-gamma mRNA in tumor-infiltrating mononuclear cells (TIM). Although anti-NK1 Ab pretreatment in vivo abrogated IFN-gamma mRNA expression and IFN-gamma production of TIM, NK cell depletion alone by anti-ASGM1 Ab pretreatment retained IFN-gamma mRNA expression and partly inhibited IFN-gamma production of TIM. Peritoneal NK cells as well as NK1.1(+) T cells but not NK1.1(-) T cells of 3LL cell- or EL4 cell-injected mice showed cytotoxicities against the same tumor cells. Further, either anti-IL-12 Ab or anti-IFN-gamma Ab ip injection significantly shortened EL4 cell-inoculated mouse survival time. Our findings suggest that peritoneal macrophages activated by tumors produce IL-12 which activates NK cells and NK1.1(+) T cells to produce IFN-gamma and both NK cells and NK1.1(+) T cells are important in suppressing the growth of the intraperitoneal tumors.

Animals↗

PubMed1999

Abundance of NKT cells in the salivary glands but absence thereof in the liver and thymus of aly/aly mice with Sjögren syndrome.

It is known that ALY/Nsc Jcl-aly/aly (aly/aly) mice that congenitally lack lymph nodes fall victim to Sjögren syndrome as a function of age. We investigated how TCRint cells of extrathymic origin and TCRhigh cells of thymic origin are distributed in various organs of these mice. Although the distribution of T-cell subsets was not different between control aly/+ and aly/aly mice in youth in any of the tested organs, the proportion of TCRint cells in the liver and spleen of aly/aly mice increased with aging. Usually, TCRint cells in the liver comprise a half-and-half mixture of a NK1. 1(+) subset (i.e., NKT cells) and a NK1.1(-) subset. In constrast, almost all expanding TCRint cells in various immune organs of aly/aly mice were found to be NK1.1(-). A large proportion of lymphocytes, including NK cells and TCRint cells, were also present in the salivary glands of aly/aly mice. Interestingly, these TCRint cells in the salivary glands contained an NK1.1(+) subset (i.e., NKT cells) that used an invariant chain of Valpha14Jalpha281 for TCRalphabeta (>50%). Moreover, gammadeltaT cells that used Vgamma 1, 2, 4/Vdelta 1, 4, 6 mRNAs, different from those of gammadeltaT cells in the liver and intestine, were abundant. Possibly reflecting the in situ generation of these T cells in the salivary glands, the expression of RAG-2 mRNA was evident by the RT-RCR method. These results suggest that (i) inflammatory lymphocytes that evoke Sjögren syndrome in aly/aly mice are NK cells or TCRint cells (both NK1.1(+) and NK1.1(-) subsets) and (ii) TCRint cells in the salivary glands might be generated in situ.

Animals↗

PubMed1999

Consistent infiltration of thymus-derived T cells into the parenchymal space of the liver in normal mice.

We previously reported that extrathymic T cells (intermediate T-cell receptor cells [TCR(int) cells]) are in situ generated in the parenchymal space of the liver in mice. They subsequently migrate to the sinusoidal lumen. In this study, we characterized how such extrathymic T cells, natural killer (NK) cells, and thymus-derived T cells (high T-cell receptor cells [TCR(high) cells]) localized in the parenchymal space or the sinusoidal lumen of mice. To this end, liver irrigation with physiological saline from the portal vein was performed and the distribution of lymphocyte subsets was compared between the liver (i.e., lymphocytes in the parenchymal space) and the irrigation solution (i.e., lymphocytes in the sinusoidal lumen). Extrathymic T cells and NK cells were found to be abundant in both the liver and sinusoidal lumen. As expected, thymus-derived T cells were abundant in the sinusoidal lumen. However, a significant proportion of thymus-derived T cells were always present in the parenchymal space, even after intensive irrigation with or without collagenase. These results suggest that thymus-derived T cells may consistently infiltrate the parenchymal space from the sinusoidal lumen in normal mice. This possibility was confirmed by (1) the injection of B6 splenic cells (TCR(high) cells) or the thymus graft into B6-nu/nu mice (presence of only TCR(int) cells) and by (2) using parabiotic mice of B6.Ly5.1 and B6.Ly5.2 strains (sharing circulation) in conjunction with immunofluorescence tests and immunohistochemical staining. In other words, inverted routes of migration and homing between extrathymic T cells and thymus-derived T cells exist in the liver.

Animals↗

PubMed1999

Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis.

BACKGROUND/AIMS: Liver natural killer 1.1 antigen (NK1)+ T cells and IL-4 play a crucial role in concanavalin-A (Con-A)-induced hepatic injury in mice, and a T helper (Th) 2 immune response was thus suggested to be involved. This study was designed to examine the effect of bacterial lipopolysaccharide (LPS), a strong inducer of a Th 1 immune response, on Con-A hepatic injury and also to clarify further the cytokine milieu of Con-A hepatitis. METHODS: LPS were injected into mice before Con-A injection to evaluate the effect on hepatic injury. The effect of the pretreatment with various T1 and Th2 cytokines or anti-cytokine antibodies on Con-A hepatitis was also examined. RESULTS: LPS in quantities > or = 500 ng/mouse, when injected 24 h before Con-A injection, abrogated the Con-A-induced elevation of transaminases, hepatocyte destruction and serum IL-4 elevation. This LPS inhibitory effect was blocked when the mice were injected with either anti-IL-6 antibody before LPS injection or IL-4 before Con-A injection. IL-6, but neither IL-10 nor IL-12 pretreatment suppressed Con-A-induced IL-4 production and hepatitis. NK1+ T cells produced IL-4 while both NK1+ T cells and NK1- T cells produced IFN-gamma. Not only anti-IL-4 antibody but also the anti-IFN-gamma antibody pretreatment inhibited Con-A hepatitis. However, although the anti-IL4 antibody suppressed IL-4 alone, the anti-IFN-gamma Ab unexpectedly inhibited both IFN-gamma and IL-4 elevation, while IL-4 injection evoked a moderate Con-A hepatitis even in the anti-IFN-gamma antibody-treated mice. Furthermore, the IL-4 mutant mice did not develop Con-A hepatitis. CONCLUSION: LPS inhibited Con-A hepatitis by inducing IL-6 and thereby inhibited IL-4 synthesis from NK1+ T cells. Although both IL-4 and IFN-gamma were required for the full induction of Con-A hepatic injury, exogenous IL-4 evoked a moderate Con-A hepatitis, even in the absence of IFN-gamma.

Animals↗

PubMed1999

Development of intraepithelial T lymphocytes in the intestine of irradiated SCID mice by adult liver hematopoietic stem cells from normal mice.

BACKGROUND/AIMS: We recently reported the adult mouse liver to contain c-kit+ stem cells that can give rise to multilineage leukocytes. This study was designed to determine whether or not adult mouse liver stem cells can generate intraepithelial T cells in the intestine as well as to examine the possibility that adult liver c-kit+ stem cells originate from the fetal liver. METHODS: Adult liver mononuclear cells, bone marrow (BM) cells, liver c-kit+ cells or bone BM c-kit+ cells of BALB/c mice were i.v. transferred into 4 Gy irradiated CB17/-SCID mice. In other experiments, fetal liver cells from Ly5.1 C57BL/6 mice and T cell depleted adult BM cells from Ly5.2 C57BL/6 mice were simultaneously transferred into irradiated C57BL/6 SCID mice (Ly5.2). At 1 to 8 weeks after cell transfer, the SCID mice were examined. RESULTS: Not only BM cells and BM c-kit+ cells but also liver mononuclear cells and liver c-kit+ cells reconstituted gamma delta T cells, CD4+ CD8+ double-positive T cells and CD8 alpha+beta- T cells of intestinal intraepithelial lymphocytes of SCID mice. Injection of a mixture of fetal liver cells from Ly5.1 C57BL/6 mice and adult BM cells from Ly5.2 C57BL/6 mice into Ly5.2 C57BL/6 SCID mice induced both Ly5.1 and Ly5.2 T cells, while also generating c-kit+ cells of both Ly5.1 and Ly5.2 origins in the liver. CONCLUSIONS: Adult mouse liver stem cells were able to generate intestinal intraepithelial T cells of the SCID mice, and it is thus suggested that some adult liver stem cells may indeed be derived from the fetal liver.

Animals↗

PubMed1999

Mice with early onset of death (EOD) due to lupus glomerulonephritis.

Both MRL-lpr/lpr (lpr) and BXSB mice fall victim to autoimmune disease as a function of age. To combine their properties, brother-sister mating of (female lpr x male BXSB)F1 mice was done. Mice for mating were selected according to indicators of early onset of glomerulonephritis and subsequent early death (i.e., EOD). This mating was continued for more than 16 generations. The EOD mice thus established had homozygous H-2k/k, lpr/lpr, and possible yaa/- (in the case of males). The average life span of males was 83 days while that of females was 126 days. After 12 weeks of age, the majority (> 80%) of male EOD mice were characterized by the abnormality of urine due to glomerulonephritis. We then characterized how glomerulonephritis was evoked, especially in terms of expanding lymphocyte subsets in various immune organs. Similar to the case of parental lpr mice, the major expanding cells were CD4-8-B220+ TCRint cells in the immune organs and kidney. In addition, myeloid cells were found to infiltrate the kidney. This massive infiltration of both TCRint cells and myeloid cells might be responsible for the onset of acute glomerulonephritis. Even after more than 50 generations, these EOD mice still carry both lpr and yaa genes. These results suggest that EOD mice might be a very useful tool for the study of acute lupus glomerulonephritis which is evoked by the genetic abnormalities.

Acute Disease↗

PubMed1999

Quick recovery in the generation of self-reactive CD4low natural killer (NK) T cells by an alternative intrathymic pathway when restored from acute thymic atrophy.

The thymus comprises the mainstream of T cell differentiation which produces conventional T cells and an alternative pathway which produces primordial T cells with intermediate density of T cell receptor (TCR)-CD3 complex on the surface (i.e. intermediate TCR cells or TCRint cells). We induced acute thymic atrophy in mice by an administration of hydrocortisone (10 mg) or irradiation (6.5 Gy). It was demonstrated that CD3intCD4lowNK1.1+ T cells were immediately generated by an alternative intrathymic pathway without passing through the double-positive CD4+8+ stage, when restored from thymic atrophy (days 3-14). These CD3intCD4lowNK1.1+ T cells mediated self-reactivity and appeared even in the periphery. mRNA of an invariant chain of TCR Valpha14Jalpha281 gene product was detected in these CD4low T cells, but not remaining CD4high T cells. The mainstream of T cell differentiation in the thymus was not restored up to day 14 and there was no leakage of self-reactive clones into the population generated through the mainstream. These results reveal that an alternative intrathymic pathway is associated with the generation of self-reactive T cells, in an early restoration phase after thymic atrophy.

Acute Disease↗

PubMed1999

Regulation of intrinsic terminator by translation in Escherichia coli: transcription termination at a distance downstream.

BACKGROUND: Rho-independent terminators in Escherichia coli are DNA sequences of 30-50 bp consisting of a GC-rich dyad symmetry sequence followed by a run of T residues in the nontemplate strand. The transcription termination at the Rho-independent terminator occurs within the T-tract in vitro. It has been believed that the transcription termination at the Rho-independent terminator occurs within the T-tract in vivo, as established in vitro, and therefore the 3' ends of mRNAs are mostly generated as a direct result of transcription termination. However, how the transcription termination occurs and how the 3' ends of mRNAs are formed in living cells remains to be studied. RESULTS: We developed a double terminator system in which a second Rho-independent terminator was placed downstream of the crp terminator. This system made it possible to detect transcripts that pass through the crp terminator by Northern blotting. We found that most of the crp transcripts extend beyond the crp terminator. The transcriptional read-through at the crp terminator was reduced when the translation of crp mRNA was interrupted. The level of the read-through transcript decreased with distance between the two terminators, suggesting that transcription termination occurs at multiple positions beyond the crp terminator. CONCLUSION: We conclude that most RNA polymerase reads through the crp terminator in the natural situation and terminates transcription over a wide region downstream of the crp terminator, resulting in heterogeneous primary transcripts that are subsequently processed back to the terminator hairpin. We propose that ribosome translation to the crp stop codon causes read-through of the terminator. The regulatory effect of translation on Rho-independent termination may be a general phenomenon at other operons.

Base Sequence↗

PubMed1999

Extrathymic derivation of gut lymphocytes in parabiotic mice.

In adult mice, c-kit+ stem cells have recently been found in their liver, intestine and appendix, where extrathymic T cells are generated. A major population of such thymus-independent subsets among intraepithelial lymphocytes is T-cell receptor (TCR)gamma delta+ CD4- CD8alpha alpha+(beta-) cells, but the origins of other lymphocyte subsets are still controversial. In this study, we examined what type of lymphocyte subsets were produced in situ by such stem cells in the small intestine, large intestine and appendix. To investigate this subject, we used parabiotic B6.Ly5.1 and B5.Ly5. 2 mice which shared the same circulation by day 3. The origin of lymphocytes was identified by anti-Ly5.1 and anti-Ly5.2 monoclonal antibodies in conjunction with immunofluorescence tests. Lymphocytes in Peyer's patches and lamina propria lymphocytes (especially B cells and CD4+ T cells) in the small intestine became a half-and-half mixture of Ly5.1+ and Ly5.2+ cells in each individual of parabiotic pairs of mice by day 14. However, the mixture was low in CD8alpha alpha+, CD8alpha beta+ and gamma delta T cells in the small and large intestines and in CD3+ CD8+ B220+ cells in the appendix. These cells might be of the in situ origin. When one individual of a pair was irradiated before parabiosis, the mixture of partner cells was accelerated. However, a low-mixture group always continued to show a lower mixture pattern than did a high-mixture group. The present results suggest that extrathymic T cells in the digestive tract may arise from their own pre-existing precursor cells and remain longer at the corresponding sites.

Animals↗

PubMed1999

Enrichment of c-kit+ Lin- haemopoietic progenitor cells that commit themselves to extrathymic T cells in in vitro culture of appendix mononuclear cells.

The appendix as well as the small intestine have recently been found to carry c-kit+ stem cells which give rise to extrathymic T cells. In this study, the properties of c-kit+ stem cells in the appendix of mice were further characterized. When appendix mononuclear cells (MNC) were cultured in the presence of stem cell factor, interleukin-3, interleukin-6 and erythropoietin on a methylcellulose culture plate, the population of c-kitdull Lin- and that of c-kithi Lin- cells expanded. Morphological study revealed that these c-kithi Lin- cells were basophilic granular cells (possibly mast cells). Both populations of cultured appendix MNC were then injected into severe combined immunodeficient mice or cultured with Tst-4 thymic stroma cells. These in vivo and in vitro studies demonstrated that c-kitdull Lin- cells were oligopotent haemopoietic progenitor cells which gave rise to extrathymic T cells, while c-kithi Lin- cells lacked haemopoietic progenitor cell activity. In contrast to c-kit+ stem cells in the bone marrow, those in the appendix did not give rise to myeloid cells and conventional thymic T cells under any of the conditions tested. The present results suggest that the appendix primarily comprises c-kit+ cells which give rise to basophilic granular cells and extrathymic T cells and that such c-kit+ cells have the ability to replicate themselves in culture in vitro.

Animals↗

PubMed1999

TNF-alpha, nitric oxide and IFN-gamma are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii.

We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4+ T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.

Administration, Oral↗