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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although neutrophils have been implicated in the hepatic injury elicited by gut ischemia/reperfusion (I/R), the contribution of other leukocyte populations to this injury process remains unclear. The objective of this study was to determine whether lymphocytes contribute to gut I/R-induced microvascular dysfunction and inflammatory responses in the liver. Intravital videomicroscopy was used to monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine nucleotide (NADH) autofluorescence in livers of wild-type, SCID, and interferon-gamma (IFN-gamma) knockout mice exposed to 15 min of gut ischemia and 1 h of reperfusion. In wild-type mice, gut I/R elicited significant increases in the number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF-alpha levels. All of these responses were profoundly attenuated in SCID mice, while only some of the responses (in the midzonal region) were blunted in IFN-gamma knockout mice. Reconstitution (24 h before ischemia) of the circulating lymphocyte pool with T-cell enriched splenocytes, but not T cell deficient (from nude mice), CD4+ T-cell depleted splenocytes or splenocytes derived from IFN-gamma knockout mice, allowed the SCID mice to respond to gut I/R in a manner similar to wild-type mice. Some of the responses were restored following reconstitution with CD8+ T-cell depleted splenocytes. These findings implicate CD4+ T-lymphocytes and IFN-gamma in the hepatic microvascular dysfunction and inflammatory cell accumulation elicited by gut I/R.
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PMID:T-lymphocytes contribute to hepatic leukostasis and hypoxic stress induced by gut ischemia-reperfusion. 1065 78

Productive infection with herpes simplex virus (HSV) type 1 is limited by both innate and adaptive immune mechanisms. The purpose of the current study was to determine whether these mechanisms also play a role in the establishment of latent HSV infection. First we examined the trigeminal ganglia (TG) of severe combined immunodeficiency (SCID), interferon-gamma knockout (GKO), and beige (a strain deficient in natural killer cell activity) mice following ocular inoculation with HSV. Although infection of SCID mice was invariably lethal, we consistently found latently infected neurons in the TG of these animals at 2-4 days postinoculation. HSV infection of GKO and beige mice, while not lethal, was characterized by a greater number of productively infected TG neurons and/or a delay in the time to peak productive infection compared to C57BL/6 controls. However, as assayed by both in situ hybridization for LAT expression and quantitative PCR (Q-PCR) for viral DNA, we found that HSV established a latent infection in GKO and beige mice as efficiently as in C57BL/6 controls. We subsequently examined the TG of "HSV-sensitive" strains of mice (Swiss-Webster, CBA, and BALB/c) following ocular infection with HSV. At the peak of acute ganglionic infection the number of productively infected TG neurons in each of these mouse strains was about sevenfold greater than in the "HSV-resistant" strain C57BL/6, consistent with previously reported differences in susceptibility to lethal challenge with HSV. However, as assayed by both in situ hybridization for LAT and Q-PCR for viral DNA, we found that HSV established a latent infection in Swiss-Webster, CBA, and BALB/c mice as efficiently as in C57BL/6 controls. We conclude that HSV efficiently establishes latent infection in the TG of mice in the absence of innate and adaptive immune mechanisms that are essential for limiting productive viral infection.
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PMID:Establishment of latent herpes simplex virus type 1 infection in resistant, sensitive, and immunodeficient mouse strains. 1068 23

Mucosal candidosis is common in acquired immune deficiency syndrome (AIDS) patients, where there is extensive mucosal involvement, but rarely dissemination. To mimic this disease, SCID mice were inoculated orally with Candida albicans, which could be recovered from standardized tissue samples of the esophagus, stomach, small intestine and caecum of all mice. Treatment with fluconazole at 5 or 10 mg kg(-1) per day were equivalent to each other and efficacious in reducing the fungal burden from all four tissues compared with no treatment or lower doses of fluconazole (P < 0.01-0.001). Fluconazole at 5 or 10 mg kg(-1) reduced fungal burden in the stomach by about 200 or 580-fold, respectively, and by approximately 25-fold in the other tissues, with 80 or 100% of mice cleared of esophageal infection, and 40 or 80% cleared of infection in the small intestine, respectively; the same doses cleared < or =20% of stomach infection and none of caecal infection. Treatment with recombinant human granulocyte colony-stimulating factor (G-CSF) up to 500 microg kg(-1) per day or 10(5) U of murine interferon-gamma (IFN-gamma) alone was ineffective, nor were combinations with a suboptimal dose fluconazole synergistic. Overall, fluconazole had dose-responsive efficacy, whereas neither G-CSF nor IFN-gamma alone or in combination with fluconazole improved efficacy. These studies demonstrate the utility of this model for examining antifungal efficacy in a situation that mimics clinical disease in AIDS patients.
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PMID:Treatment of orogastrointestinal candidosis in SCID mice with fluconazole alone or in combination with recombinant granulocyte colony-stimulating factor or interferon-gamma. 1089 89

A weakness of the hu-PBL-SCID model for the study of human immune functions is the appearance of anergy and the consequent loss of T cell function. We demonstrate here that human T cells retain normal functions during the early stage of chimerism. At 1 and 2 weeks post-engraftment, T cells isolated from the peritoneal cavity of hu-PBL chimeras could be activated and proliferated upon stimulation with phytohaemagglutinin (PHA) or specific antigens to which the cell donor was known to be immune. T cells derived from hu-PBL-SCID and hu-PBL-NOD/LtSz-scid (NOD/SCID) mice not only proliferated but also produced interferon-gamma (IFN-gamma) and IL-5 following in vitro stimulation with tetanus toxoid (TT) or hepatitis B surface antigen (HBsAg). These antigen-specific T cells could only be demonstrated when cognate antigen was administered together with or immediately following the PBL transfer. Without an early rechallenge with antigen in vivo, no TT- or HBsAg-specific T cell responses could be elicited, showing the vulnerability and antigen-dependence of the T cell response. Vigorous anti-TT or anti-HBs responses could be observed in all chimeras. Administration of antigen together with the PBL graft enhanced the humoral anti-TT response in SCID and NOD/SCID mice but had little effect on the anti-HBs antibody response in NOD/SCID mice. These data confirm the observation that the B cell compartment in hu-PBL-SCID chimera is largely antigen-independent and extend this to SCID/NOD.
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PMID:Antigen-specific T cell responses in human peripheral blood leucocyte (hu-PBL)-mouse chimera conditioned with radiation and an antibody directed against the mouse IL-2 receptor beta-chain. 1101 27

Shepard's technique for growth of Mycobacterium leprae in the mouse footpad, described in 1960, and more recent studies in thymectomized-irradiated mice and rats, athymic nude mice, nude rats and severe combined immunodeficiency (SCID) mice have defined the role of T-cell mediated immunity (CMI) in leprosy. However, the normal mouse and the immunocompromised mouse and rat represent only elements of polar tuberculoid disease and polar lepromatous leprosy, respectively. Transgenic, knockout (KO) mice may be employed to study the roles of individual genes in the ability of the host to mount an effective immune response to pathogens, and may also allow development of mouse models for the immunologically unstable borderline areas of the spectrum. We are exploiting certain KO mice to improve our understanding of CMI to M. leprae, and to study the role of the microenvironment of the leprosy granuloma in pathogenesis. CGD (chronic granulomatous disease) mice and iNOS-KO mice lack the ability to produce reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), respectively, whereas the T cells of GKO mice are unable to produce interferon-gamma (IFN gamma). iNOS-KO mice exhibit an enhanced capacity to form granulomas, and the histopathology of the infected footpad tissues of this strain share many elements of borderline tuberculoid disease. The macrophages of CGD mouse kill or inhibit multiplication of M. leprae, although they lack ROI. Multiplication of the organisms in the footpad is enhanced in GKO mice, although these mice retain some host resistance. In addition, we have been investigating supplementary, conditional approaches to KO mouse models. For example, the down-regulatory effects of local prostaglandin production can be controlled with essential fatty acid deficient diets or indomethacin, RNI can be blocked in CGD and GKO mice by treatment with aminoguanidine, NG monomethyl arginine or N6-(1-iminoethyl)-L-lysine, and local elaboration of TNF alpha can be neutralized by anti-TNF alpha antibody or excess TNF alpha receptor. Other cytokines can be neutralized by antibody as well, broadening the range of conditional knockout models.
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PMID:Exploitation of gene knockout mice models to study the pathogenesis of leprosy. 1120 77

Blast cells from patients with acute myeloid leukemia (AML) commonly express CD64, the high-affinity receptor for immunoglobulin G (FcgammaRI). An immunotoxin (MDX-44) was constructed by coupling humanized anti-CD64 monoclonal antibody (mAb) H22 via a bivalent linker to deglycosylated ricin A-chain (RA). Human leukemia cell lines were incubated with MDX-44 or H22/free RA. The effect of MDX-44 on the proliferation of leukemia cells was assessed by [(3)H]thymidine incorporation. In the presence of interferon-gamma (IFN-gamma), MDX-44 significantly inhibited the proliferation of CD64(+) HL-60, NB4, and U937 cells in 72-h cultures in a dose-dependent manner. The mechanism of action appeared to be the induction of apoptosis, as measured by propidium iodide staining and flow cytometry analysis. However, CD64(-) KG-1a and Daudi cells were not affected by MDX-44/IFN-gamma. Incubating HL-60 cells with MDX-44/IFN-gamma resulted in a 99% decrease in colony-forming units, whereas colony-forming cells in normal bone marrow were not significantly suppressed by such treatment. Cells from 60% of AML patients (6/10) were inhibited by MDX-44/IFN-gamma, and the inhibition was correlated with CD64 expression on these cells (r = 0.65). In a human AML model in NOD/SCID mice, MDX-44/IFN-gamma inhibited 95-98% of peritoneal exudate AML cell proliferation and 85-90% of solid leukemia masses. The effect of MDX-44 on AML cells was dependent on activation of cells by IFN-gamma. MDX-44/IFN-gamma may have value in the therapy of AML cells expressing cell-surface CD64.
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PMID:Cytotoxicity of anti-CD64-ricin a chain immunotoxin against human acute myeloid leukemia cells in vitro and in SCID mice. 1127 63

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.
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PMID:Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. 1128 72

We previously reported that T cells from aged mice were resistant to activation-induced cell death (AICD) in vitro. To determine whether the presence of AICD-resistant T cells is associated with defects in age-related peripheral clonal deletion in vivo, congenic male SCID mice were reconstituted with T cells from aged or young female D(b)/H-Y TCR (Tg71) transgenic mice. Compared with recipients of young cells, the recipients of T cells from aged mice exhibited a 3-fold increase in the percentage of autoreactive CD8(+) H-Y antigen-reactive T cells as defined by the clonotypic antibody, M33. There were significantly increased sera levels of interferon-gamma, a significantly decreased expression of FasL by M33(+)CD8(+) T cells, and significantly decreased apoptosis by DNA fragmentation staining of the spleen of mice reconstituted with T cells from aged mice compared to those from young mice. By day 21, the recipients of T cells from aged mice but not young mice, exhibited infiltration of CD3(+) cells into the non-lymphoid organs. These results indicate that there is defective peripheral deletion of the self-reactive T cells derived from aged female Tg71 mice, and that failure to delete these cells is associated with the defective T-cell clonal deletion in the recipient mice.
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PMID:Aged mice exhibit in vivo defective peripheral clonal deletion of D(b)/H-Y reactive CD8(+) T cells. 1131 18

A 70 kDa heat shock protein (HSP70) has been reported previously to be strongly expressed in virulent Toxoplasma gondii strains taken from immunocompetent mice but it is poorly expressed by virulent parasites in mice immunocompromised by treatment with cortisone acetate or by virulent parasites cultured in vitro. Immune factors such as interferon-gamma, tumour necrosis factor and reactive nitrogen intermediates derived from nitric oxide are known to be important inducers of HSP70 production and are also known to be produced during the immune response to acute T. gondii infection. The ability of these immune factors to induce T. gondii HSP70 production was tested by analysing HSP70 production in tachyzoites of the virulent RH strain of T. gondii recovered from mice deficient in: (1) T cells (nude mice); (2) T and B cells (SCID mice); (3) interferon-gamma receptors (interferon-gamma receptor knockout mice); and (4) tumour necrosis factor receptors (tumour necrosis factor receptor knockout mice). Parasites from nude and SCID mice produced as much HSP70 as immunocompetent mice. Likewise, T. gondii tachyzoites from mice lacking receptors for interferon-gamma or tumour necrosis factor produced HSP70 in quantities similar to wild-type mice. The ability to produce reactive nitrogen intermediates in response to T. gondii infection, as detected by elevated levels of nitrate and nitrite in sera, was normal in tumour necrosis factor receptor knockout mice but was completely lacking in interferon-gamma receptor knockout mice, indicating that reactive nitrogen intermediates are also not responsible for induction of parasite HSP70. Thus, immune factors that induce HSP70 production in mammalian cells do not appear to play primary roles in inducing HSP70 production by T. gondii.
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PMID:The production of a 70 kDa heat shock protein by Toxoplasma gondii RH strain in immunocompromised mice. 1142 37

Tolerance to self-antigens is an ongoing process that begins centrally during T-cell maturation in the thymus and continues throughout the cell's life in the periphery by a network of regulated restraints. Remaining self-reactive T-cells that escape intrathymic deletion may be silenced within the peripheral immune system by specialized regulatory CD4+ cells. By analogy, regulatory CD4+ cells that control immunity to "acquired self" should arise in circumstances where the immune system acquires tolerance to foreign MHC, such as the tolerance that develops following the exposure to foreign MHC antigens during the neonatal period. We have used this classic model of neonatal tolerance to examine the role of regulatory CD4+ cells in acquired tolerance to disparate class I and class II MHC. Adoptive transfer of unfractionated but not CD4+-depleted spleen cells from neonatal tolerant mice into SCID recipients inhibited skin graft rejection by immunocompetent CD8+ T cells. Using 5-bromo-2'-deoxyuridine incorporation, standard cytotoxic T-lymphocyte assays, short-term interferon-gamma ELISPOT, and intracellular FACS analysis to study CD8+ T-cell effector function, we demonstrated that neonatal tolerant mice contain CD4+CD25+ cells that suppress the development of anti-donor CD8+ T-cell responses in vitro. We conclude that regulatory CD4+CD25+ cells initiate and/or maintain tolerance by preventing the development of CD8+ T-cell alloreactivity.
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PMID:CD4+CD25+ regulatory cells in acquired MHC tolerance. 1172 27


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