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Biomedical subjects

M Suresh

Publications and source records attributed to M Suresh.

At least 37 records · Page 2Linked to original sources
PubMed2004

Dissection of antiviral and immune regulatory functions of tumor necrosis factor receptors in a chronic lymphocytic choriomeningitis virus infection.

The effector function of CD8 T cells is mediated via cell-mediated cytotoxicity and production of cytokines like gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). While the roles of perforin-dependent cytotoxicity, IFN-gamma, and TNF-alpha in controlling acute viral infections are well studied, their relative importance in defense against chronic viral infections is not well understood. Using mice deficient for TNF receptor (TNFR) I and/or II, we show that TNF-TNFR interactions have a dual role in mediating viral clearance and downregulating CD8 and CD4 T-cell responses during a chronic lymphocytic choriomeningitis virus (LCMV) infection. While wild-type (+/+) and TNFR II-deficient (p75(-/-)) mice cleared LCMV from the liver and lung, mice deficient in TNFR I (p55(-/-)) or both TNFR I and TNFR II (double knockout [DKO]) exhibited impaired viral clearance. The inability of p55(-/-) and DKO mice to clear LCMV was not a sequel to either suboptimal activation of virus-specific CD8 or CD4 T cells or impairment in trafficking of LCMV-specific CD8 T cells to the liver and lung. In fact, the expansion of LCMV-specific CD8 and CD4 T cells was significantly higher in DKO mice compared to that in +/+, p55(-/-), and p75(-/-) mice. TNFR deficiency did not preclude the physical deletion of CD8 T cells specific for nucleoprotein 396 to 404 but delayed the contraction of CD8 T-cell responses to the epitopes GP33-41 and GP276-285 in the viral glycoprotein. The antibody response to LCMV was not significantly altered by TNFR deficiency. Taken together, these findings have implications in development of immunotherapy in chronic viral infections of humans.

Animals↗
PubMed2003

Equine platelet CD62P (P-selectin) expression: a phenotypic and morphologic study.

Acute inflammatory diseases, such as colic, septicemia and endotoxemia are common in equines and have been shown to be correlated to vascular injury and thrombosis. In humans with similar thrombotic conditions, P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1)-mediated platelet-leukocyte adhesion contributes to the pathogenesis of these disorders through the generation of inflammatory mediators and tissue factor. As such, we hypothesized that a P-selectin-PSGL-1 (platelet-leukocyte) interaction, similar to that in humans, may also exist in the horse. The objective of this study was to investigate phenotypic and morphological properties of equine platelet activation with a focus on CD62P (P-selectin) expression and CD62P mediated platelet-leukocyte interactions. To study high levels of platelet activation, we used 1 U/ml thrombin to induce secondary, irreversible aggregation in both human and equine platelets. Addition of glycyl-L-prolyl-L-arginyl-L-proline amide (GPRP) prior to thrombin activation blocked fibrin polymerization, allowing the use of flow cytometry to study alpha-granule expression as a measure of platelet activation. Thrombin activation resulted in high levels of activation, measured as P-selectin expression, in both humans and equines. Interestingly, our research illustrates that in healthy horses, P-selectin is also constitutively expressed on 20-25% of resting platelets. This finding is in direct contrast to humans, in which P-selectin expression is negligible (<5%) in the absence of agonist activation. The high baseline level of P-selectin expression among equine platelets may suggest that they are primed for leukocyte adhesion, possibly resulting in prothrombotic conditions. This phenomenon could be of significant clinical relevance, as it may be related to the rapid clinical decline often seen in equine patients with colic and endotoxemia, where vascular injury and thrombotic complications compromise patient survival. Based on these findings, further investigation into the mechanisms of platelet P-selectin-mediated inflammation and platelet-leukocyte mediated vascular injury in the horse appears warranted.

Animals↗
PubMed2003

Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection.

In addition to its established role in innate immune mechanisms, complement component C3 is also of critical importance in B cell activation and T cell-dependent Ab responses. In this study, we have examined the requirement for C3 in the generation of primary CD8 T cell responses to an acute systemic viral infection. We compared Ag-specific CD8 T cell responses to lymphocytic choriomeningitis virus (LCMV) between wild-type (+/+) and C3-deficient (C3(-/-)) mice on both 129/B6 and B6 backgrounds. These studies revealed that C3 activity is required for optimal expansion of LCMV-specific effector CD8 T cells in an epitope-dependent fashion, which is influenced by the genetic background of the mice. Studies in complement receptor 1/2 (CR1/CR2)-deficient mice showed that regulation of LCMV-specific CD8 T cell responses by C3 is not dependent upon CR1/CR2. These findings may have implications in vaccine development, therapy of autoimmune diseases, and prevention of graft rejection.

Acute Disease↗
PubMed2002

CD4+ TCR repertoire heterogeneity in Schistosoma mansoni-induced granulomas.

The hallmark of Schistosoma mansoni infection is the formation of liver granulomas around deposited ova. The initiation of granuloma formation is T cell-dependent since granulomas are not formed in their absence. We investigated whether a few T cells arrive to initiate the inflammatory lesion and subsequently expand locally, or whether a large repertoire of systemically activated T cells home to the delayed type hypersensitivity reaction induced by the ova. The TCR repertoire of single granulomas from the same liver were analyzed by PCR using Vbeta-specific primers and CDR3 analysis. Each granuloma has a very diverse TCR repertoire indicating that most of the T cells recruited to these lesions are activated systemically. At the same time, sequence analysis of individually sized CDR3 products from single granuloma indicate that a fraction of T cells expand locally at the lesion site. Using TCR transgenic mice containing a pigeon cytochrome c-specific T cell population or lymphocytic choriomeningitis virus infection tracked with lymphocytic choriomeningitis virus-specific tetramers, we demonstrated that nonspecific T cells home to the granuloma if they are activated. However, recombinase-activating gene 2(-/-) pigeon cytochrome c-specific TCR transgenic mice fail to form granulomas in response to S. mansoni ova even after T cell activation, suggesting a requirement for egg-specific T cells in the initiation of these inflammatory lesions. Understanding the mechanism of T cell recruitment into granulomas has important implications for the rational design of immunotherapies for granulomatous diseases.

Animals↗
PubMed2002

Role of cell cycle regulator p19ARF in regulating T cell responses.

Although it is well established that the processes of cellular proliferation and apoptosis are linked, the role of cell cycle regulators in T cell responses in vivo is not well understood. In recent years, tumor suppressor molecule p19(ARF) has emerged as a key cell cycle regulator important in cellular apoptosis against strong mitogenic stimuli. In this study, we compared the antigen-specific T cell responses between wild type (+/+) and p19(ARF)-deficient (p19-/-) mice following an acute infection with lymphocytic choriomeningitis virus (LCMV). p19-/- mice mounted a potent CD8 T cell response and the magnitude of expansion of LCMV-specific CD8 T cells was comparable to that of +/+ mice. Further, the clonal downsizing of the expanded virus-specific CD8 T cells and establishment of long-term T cell memory were minimally affected by p19(ARF) deficiency. Therefore, p19(ARF) function is not essential to regulate T cell responses following an acute viral infection.

Acute Disease↗
PubMed2002

Role of lymphotoxin alpha in T-cell responses during an acute viral infection.

The importance of lymphotoxin alpha (LTalpha) in lymphoid organogenesis is well established. Although LTalpha has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LTalpha in T-cell activation and effector function in vivo is not well understood. To determine the role of LTalpha in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type (+/+) and LTalpha-deficient (LTalpha(-/-)) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LTalpha(-/-) mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LTalpha(-/-) mice also contained substantially lower number of LCMV-specific CD8 T cells than those of +/+ mice. Greatly reduced virus-specific CD8 T-cell responses in LTalpha(-/-) mice led to a defect in LCMV clearance from the tissues. In comparison to that in +/+ mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LTalpha(-/-) mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LTalpha(-/-) mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into +/+ mice, the activation and expansion of LCMV-specific LTalpha(-/-) T cells were restored to levels comparable to those of +/+ T cells. In a reciprocal cell transfer experiment, activation of +/+ T cells was significantly reduced upon transfer into LTalpha(-/-) mice. These results showed that impairment in the activation of LCMV-specific T cells in LTalpha(-/-) mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LTalpha(-/-) T cells.

Adoptive Transfer↗
PubMed2002

Modulation of monocyte signaling and pore formation in response to agonists of the nucleotide receptor P2X(7).

Previous reports about the nucleotide receptor P2X(7), which exhibits ion channel and pore-forming activity and is known to promote IL-1beta processing, have centered largely on its role in macrophage function, whereas its participation in monocyte activity has been unclear. However, because extracellular ATP has been shown to affect monocytes with respect to IL-1beta release, we hypothesized that the P2X(7) receptor is also present and functional in a subpopulation of blood monocytes. Flow cytometric analysis revealed that about 70% of monocytes isolated from normal human donors expressed the P2X(7) receptor. Activation of P2X(7) receptor-associated pore formation by the agonist BzATP resulted in a 9- to 15-fold increase in the uptake of the membrane-impermeant fluorescent dye YO-PRO, and this dye uptake is markedly inhibited by the P2X(7) receptor antagonists KN-62 and oATP. Evidence supporting the presence of the functional P2X(7) receptor in monocytes also includes the observation that BzATP exposure results in a dose-dependent increase in the activation of mitogen-activated 2protein kinases and the nuclear translocation of the transcription factor NF-kappaB in human monocytes and in THP-1 human monocytic cells. Furthermore, treatment of monocytes with BzATP induced the expression of cyclooxygenase-2 (COX-2) and tissue factor, which are two important endpoints that have not been previously shown to be regulated by nucleotide receptor action in monocytes. Together, these data indicate that a subpopulation of human monocytes express P2X(7) receptors that are functional with respect to pore formation, signal transduction, and mediator production, further supporting a key role for this nucleotide receptor in host immune responses.

Benzoxazoles↗
PubMed2001

Role of CD28-B7 interactions in generation and maintenance of CD8 T cell memory.

Although the role of CD28-B7 interaction in the activation of naive T cells is well established, its importance in the generation and maintenance of T cell memory is not well understood. In this study, we examined the requirement for CD28-B7 interactions in primary T cell activation and immune memory. Ag-specific CD8 T cell responses were compared between wild-type (+/+) and CD28-deficient (CD28(-/-)) mice following an acute infection with lymphocytic choriomeningitis virus (LCMV). During the primary response, there was a substantial activation and expansion of LCMV-specific CD8 T cells in both +/+ and CD28(-/-) mice. However, the magnitude of the primary CD8 T cell response to both dominant and subdominant LCMV CTL epitopes was approximately 2- to 3-fold lower in CD28(-/-) mice compared with +/+ mice; the lack of CD28-mediated costimulation did not lead to preferential suppression of CD8 T cell responses to the weaker subdominant epitopes. As seen in CD28(-/-) mice, blockade of B7-mediated costimulation by CTLA4-Ig treatment of +/+ mice also resulted in a 2-fold reduction in the anti-LCMV CD8 T cell responses. Loss of CD28/B7 interactions did not significantly affect the generation and maintenance of CD8 T cell memory; the magnitude of CD8 T cell memory was approximately 2-fold lower in CD28(-/-) mice as compared with +/+ mice. Further, in CD28(-/-) mice, LCMV-specific memory CD8 T cells showed normal homeostatic proliferation in vivo and also conferred protective immunity. Therefore, CD28 signaling is not necessary for the proliferative renewal and maintenance of memory CD8 T cells.

Animals↗
PubMed2001

Emergence of Candida tropicalis as the major cause of fungaemia in India.

The fungal isolates (n = 191) from 1970 consecutive blood cultures over a 9-year period were identified. Candida tropicalis was the predominant isolate accounting for 66% of all isolates whereas Candida albicans ranked only a distant second with 21%. The difference was highly significant (P < 0.00001) The other isolates included C. parapsilosis (5.8%), C. glabrata (2.1%), C. pelliculosa (1.2%), C. lipolytica (1.0%) C. krusei (1.0%) and Trichosporon beigelii (2.6%). The isolates were obtained predominantly from postoperative patients on therapy with more than one antibiotic.

Candida↗
PubMed2000

Pathogenic avian adenovirus type II induces apoptosis in turkey spleen cells.

Wild-type mammalian adenoviruses are known to inhibit programmed cells death in infected cells. This study demonstrated for the first time that an avian type II adenovirus, the hemorrhagic enteritis virus (HEV) of turkeys, induced apoptosis in turkey spleen cells at 3 and 4 days post infection. The increased apoptosis rate in spleens of HEV-infected turkeys was associated with increased virus replication. Increased apoptosis preceded extensive virus-induced cellular necrosis. At 3 days post infection, spleen cells from HEV-infected turkeys released tumor necrosis like factor and nitric oxide inducing factors after ex vivo stimulation with concanavalin A. Spleen cells from HEV-exposed turkeys also secreted an interleukin 6-like factor when cultured in vitro. These cytokines may have contributed to HEV-pathogenesis and HEV-induced apoptosis and necrosis in the spleen. Induction of apoptosis by an avian adenovirus but not by wild-type mammalian adenoviruses indicates that evolutionarily distant adenoviruses may have different pathogenic mechanisms.

Adenoviridae Infections↗
PubMed2000

Relationship of renal dysfunction to proximal arterial disease severity in atherosclerotic renovascular disease.

BACKGROUND: Renal impairment is common in patients with atherosclerotic renovascular disease (ARVD), but its pathogenesis is uncertain. This study investigated whether any relationship existed between renal function and the severity of proximal renal arterial lesions in patients with ARVD. METHODS: A cohort of 71 patients had creatinine clearance measured at the time of digital subtraction angiography; eight patients were diabetics and were excluded from further analysis. The severity of proximal renovascular lesions was estimated by standard methodology, and patients were sub-grouped according to residual patency of the proximal renal arteries (e.g. normal=2.0; unilateral occlusion )RAO(=1.0). Renal bipolar lengths at ultrasound were also assessed. RESULTS: Sixty-three non-diabetic patients (mean+/-SD age 67.7+/-5.8 years; 34 males) were suitable for study. No differences in renal function (mean+/-SD creatinine clearance (ml/min)) were seen between patients with unilateral (32. 1+/-18.9, n=36) or bilateral (31.7+/-20.9, n=27) disease, or between sub-groups with RAS <60% (28.3+/-13.9, n=15), unilateral RAS >60% (38.9+/-24.6, n=12), bilateral RAS >60% (36.3+/-20.4, n=6) or unilateral RAO (30.3+/-17.7, n=28), and mean average renal size similarly did not differ between the sub-groups. No correlation existed between residual patency and creatinine clearance (r=0.015); mean+/-SD renal function was almost identical in the four patency sub-groups, and average renal size mirrored this pattern. Mean 24-h urinary protein excretion was similar for the four groups, but patients with minimal ARVD had significantly less comorbid vascular disease. CONCLUSIONS: These findings suggest that the severity of proximal renal artery lesions is often unrelated to the severity of renal dysfunction in patients with ARVD. Associated renal parenchymal damage is the more probable arbiter of renal dysfunction, and this should be considered when revascularization procedures are contemplated.

Aged↗
PubMed1999

Radiochemical studies of 99mTc complexes of modified cysteine ligands and bifunctional chelating agents.

The synthesis of four novel ligands using the amino-acid cysteine and its ethyl carboxylate derivative is described. The synthetic method involves a two-step procedure, wherein the intermediate Schiff base formed by the condensation of the amino group of the cysteine substrate and salicylaldehyde is reduced to give the target ligands. The intermediates and the final products were characterized by high resolution nuclear magnetic resonance spectroscopy. Complexation studies of the ligands with 99mTc were optimized using stannous tartrate as the reducing agent under varying reaction conditions. The complexes were characterized using standard quality control techniques such as thin layer chromatography, paper electrophoresis, and paper chromatography. Lipophilicities of the complexes were estimated by solvent extraction into chloroform. Substantial changes in net charge and lipophilicity of the 99mTc complexes were observed on substituting the carboxylic acid functionality in ligands I and II with the ethyl carboxylate groups (ligands II and IV). All the ligands formed 99mTc complexes in high yield. Whereas the complexes with ligands I and II were observed to be hydrophilic in nature and not extractable into CHCl3, ligands III and IV resulted in neutral and lipophilic 99mTc complexes. The 99mTc complex with ligand II was not stable and on storage formed a hydrophilic and nonextractable species. The biodistribution of the complexes of ligands I and II showed that they cleared predominantly through the kidneys, whereas the complexes with ligands III and IV were excreted primarily through the hepatobiliary system. No significant brain uptake was observed with the 99mTc complexes with ligands III and IV despite their favorable properties of neutrality, lipophilicity, and conversion into a hydrophilic species. These ligands offer potential for use as bifunctional chelating agents.

Animals↗
PubMed1999

Proteinuria in atherosclerotic renovascular disease.

Proteinuria is well described in atherosclerotic renovascular disease (ARVD), but the prevalence is unknown, and the pathogenesis may vary between patients. Substantial proteinuria (> 2 g/day) however, would be regarded by many as atypical of ARVD. We studied 94 patients (52 male) with ARVD, median age 67 years (range 49-87). Digital subtraction angiography was performed on all patients. Protein was assayed in 24-h urine samples and GFR derived using the Cockroft-Gault formula. Forty-nine patients (52%) had proteinuria < 0.5 g/24 h. Proteinuria increased with worsening renal function. Biopsies from seven non-diabetic patients with substantial proteinuria showed: minimal changes (1); glomerular sclerosis with marked ischaemic changes (3); focal glomerulosclerosis (2); and athero-emboli (1). Proteinuria, rather than being indicative of other pathology, is often a marker of severity of parenchymal disorder in atherosclerotic nephropathy, which itself is the major determinant of renal dysfunction in patients with ARVD.

Aged↗
PubMed1999

A role for perforin in downregulating T-cell responses during chronic viral infection.

Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf -/-) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf -/- mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral "exhaustion" of activated CD8 T cells occurred less efficiently in perf -/- mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf -/- mice; approximately 50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.

Animals↗
PubMed1998

Viral immune evasion due to persistence of activated T cells without effector function.

We examined the regulation of virus-specific CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Our study shows that within the same persistently infected host, different mechanisms can operate to silence antiviral T cell responses; CD8 T cells specific to one dominant viral epitope were deleted, whereas CD8 T cells responding to another dominant epitope persisted indefinitely. These virus-specific CD8 T cells expressed activation markers (CD69(hi), CD44(hi), CD62Llo) and proliferated in vivo but were unable to elaborate any antiviral effector functions. This unresponsive phenotype was more pronounced under conditions of CD4 T cell deficiency, highlighting the importance of CD8- CD4 T cell collaboration in controlling persistent infections. Importantly, in the presence of CD4 T cell help, adequate CD8 effector activity was maintained and the chronic viral infection eventually resolved. The persistence of activated virus-specific CD8 T cells without effector function reveals a novel mechanism for silencing antiviral immune responses and also offers new possibilities for enhancing CD8 T cell immunity in chronically infected hosts.

Animals↗
PubMed1998

In vivo dynamics of anti-viral CD8 T cell responses to different epitopes. An evaluation of bystander activation in primary and secondary responses to viral infection.

Viral infections induce extensive T cell proliferation in vivo. However, only a small fraction (1-5%) of the activated T cells have been shown to be virus specific leading to the prevailing notion that most of the T cell expansion represents cytokine-mediated by-stander activation and/or cross reactive stimulation of non specific cells. To re-examine this issue we quantitated antigen specific CD8 T cells during acute LCMV infection of mice using three sensitive techniques: (i) intracellular cytokine production, (ii) single cell ELISPOT and (iii) direct visualization of antigen specific CD8 T cells by staining with MHC class I tetramers + peptide. In contrast to previous estimates, we found that 50-70% of the activated CD8 T cells were LCMV specific. This represented > or = 10,000-fold increase (approximately 2 x 10(7) virus specific cells/spleen) in 8 days with the peak expansion occurring between day 3 and 5 during which period virus specific CD8 T cells had an estimated division time of approximately 8 hours. Following viral clearance, the number of antigen specific CD8 T cells dropped to 1 x 10(6) per spleen and were maintained at this level for the life of the mouse. Upon rechallenge with LCMV, memory CD8 T cells rapidly proliferated and again comprised > 50% of the total CD8 T cells. In contrast, upon challenge with a heterologous virus such as vaccinia, there was no change in the number of LCMV specific memory CTL, despite a substantial increase in the number of activated CD8 T cells. Taken together, these results show that much of the CD8 T cell expansion seen during viral infection represents antigen specific cells.

Animals↗
PubMed1998

Comparative pathogenesis of haemorrhagic enteritis virus (HEV) infection in turkeys and chickens.

The pathogenesis of haemorrhagic enteritis virus (HEV) infection in chickens 3-4 days post-infection was compared with that in turkeys. As expected, infected turkeys showed HEV-specific lesions that included enlargement and mottling of the spleen, as well as haemorrhagic enteritis. In infected chickens, only splenomegaly was observed. The number of HEV-infected cells in the spleen was significantly (P < 0.05) higher in the turkey than in the chicken. In both species, the immunohistochemical labelling of B-cell surface determinants was diminished and the splenic B-cell areas were undetectable after HEV infection. Infection with HEV resulted in an increase in nitric oxide production by macrophages in chickens but not in turkeys.

Animals↗