Host defense against Mycobacterium avium does not have an absolute requirement for major histocompatibility complex class I-restricted T cells.
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The role of CD8(+) T cells was evaluated in a mouse model of disseminated Mycobacterium avium infection. C57BL/6J and C57BL/6Jbeta2-/- (beta2-/-) mice were infected intravenously, and the number of viable bacteria in each liver and spleen was determined. No significant difference between the number of bacteria in the two strains of mice was observed at 2, 4, 6, and 8 weeks after infection. Histopathological examination of granulomas from C57BL/6J and beta2-/- mice did not show any difference either in the number of organisms per granuloma or in the size of the granulomas. Investigation of the cytokine profile in the spleen demonstrated that the beta2-/- strain of mice produced a significantly lower amount of gamma interferon at 8 weeks after infection and significantly increased concentrations of tumor necrosis factor alpha compared with that from the wild-type mouse. Interleukin-12 and transforming growth factor beta1 levels did not differ between the two strains of mice at 2, 4, 6, and 8 weeks. Although previous work had found that host response against Mycobacterium tuberculosis involves major histocompatibility complex class I-restricted T cells, our results indicate that chronic deficiency of CD8(+) T cells does not lead to a different expression of the disease and that if CD8(+) T cells are involved in the host response, their function can be assumed by other immune cells. (+info)
Change from conventional haemodiafiltration to on-line haemodiafiltration.
(26/1648)
BACKGROUND: On-line haemodiafiltration (HDF) is a technique which combines diffusion with elevated convection and uses pyrogen-free dialysate as a replacement fluid. The purpose of this study was to evaluate the difference between conventional HDF (1-3 l/h) and on-line HDF (6-12 l/h). METHODS: The study included 37 patients, 25 males and 12 females. The mean age was 56.5 +/- 13 years and duration of dialysis was 62.7 +/- 49 months. Three patients dropped out for transplantation, three patients died and three failed to complete the study period. Initially all patients were on conventional HDF with high-flux membranes over the preceding 34 +/- 32 months. Treatment was performed with blood flow (QB) 402 +/- 41 ml/min, dialysis time (Td) 187 min, dialysate flow (QD) 654 +/- 126 ml/min and replacement fluid (Qi) 4.0 +/- 2 l/session. Patients were changed to on-line HDF with the same filtre and dialysis time, QD 679 +/- 38 ml/min (NS), QB 434 +/- 68 ml/min (P < 0.05) and post-dilutional replacement fluid 22.5 +/- 4.3 l/session (P < 0.001). We compared conventional HDF with on-line HDF over a period of 1 year. Dialysis adequacy was monitored according to standard clinical and biochemical criteria. Kinetic analysis of urea and beta2-micro-globulin (beta2m) was performed monthly. RESULTS: Tolerance was excellent and no pyrogenic reactions were observed. Pre-dialysis sodium increased 2 mEq/l during on-line HDF. Plasma potassium, pre- and post-dialysis bicarbonate, uric acid, phosphate, calcium, iPTH, albumin, total proteins, cholesterol and triglycerides remained stable. The mean plasma beta2m reduction ratio increased from 56.1 +/- 8.7% in conventional HDF to 71.1 +/- 9.1% in on-line HDF (P < 0.001). The pre-dialysis plasma beta2m decreased from 27.4 +/- 8.1 to 24.2 +/- 6.5 mg/l (P < 0.01). Mean Kt/V (Daugirdas 2nd generation) was 1.35 +/- 0.21 in conventional HDF compared with 1.56 +/- 0.29 in on-line HDF (P < 0.01), Kt/Vr (Kt/V taking into consideration post-dialysis urea rebound) 1.12 +/- 0.17 vs 1.26 +/- 0.20 (P < 0.01), BUN time average concentration (TAC) 44.4 +/- 9 vs 40.6 +/- 10 mg/dl (P < 0.05) and protein catabolic rate (PCR) 1.13 +/- 0.22 vs 1.13 +/- 0.24 g/kg (NS). There was a significant increase in haemoglobin (10.66 +/- 1.1 vs 11.4 +/- 1.5) and haematocrit (32.2 +/- 2.9 vs 34.0 +/- 4.4%), P < 0.05, during the on-line HDF period, which allowed a decrease in the erythropoietin doses (3861 +/- 2446 vs 3232 +/- 2492 UI/week), (P < 0.05). Better blood pressure control (MAP 103.8 +/- 15 vs 97.8 +/- 11 mmHg, P < 0.01) and a lower percentage of patients requiring antihypertensive drugs were also observed. CONCLUSION: The change from conventional HDF to on-line HDF results in increased convective removal and fluid replacement (18 l/session). During on-line HDF treatment, dialysis dose was increased for both small and large molecules with a decrease in uraemic toxicity level (TAC). On-line HDF provided a better correction of anaemia with lower dosages of erythropoietin. Finally, blood pressure was easily controlled. (+info)
Circulating biochemical markers of bone remodeling in uremic patients.
(27/1648)
Chronic renal failure is often associated with bone disorders, including secondary hyperparathyroidism, aluminum-related low-turnover bone disease, osteomalacia, adynamic osteopathy, osteoporosis, and skeletal beta2-microglobulin amyloid deposits. In spite of the enormous progress made during the last few years in the search of noninvasive methods to assess bone metabolism, the distinction between high- and low-turnover bone diseases in these patients still frequently requires invasive and/or costly procedures such as bone biopsy after double tetracycline labeling, scintigraphic-scan studies, computed tomography, and densitometry. This review is focused on the diagnostic value of several new serum markers of bone metabolism, including bone-specific alkaline phosphatase (bAP), procollagen type I carboxy-terminal extension peptide (PICP), procollagen type I cross-linked carboxy-terminal telopeptide (ICTP), pyridinoline (PYD), osteocalcin, and tartrate-resistant acid phosphatase (TRAP) in patients with chronic renal failure. Most of the observations made by several groups converge to the conclusion that serum bAP is the most sensitive and specific marker to evaluate the degree of bone remodeling in uremic patients. Nonetheless, PYD and osteocalcin, in spite of their retention and accumulation in the serum of renal insufficient patients, are also excellent markers of bone turnover. The future generalized use of these markers, individually or in combination with other methods, will undoubtedly improve the diagnosis and the treatment of the complex renal osteodystrophy. (+info)
Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules.
(28/1648)
Recent investigations have shown that malignant transformation may down-regulate the expression of class I HLA molecules, beta2-microglobulin (beta2m) and members of the antigen-processing machinery. In the present study, we HLA-genotyped and identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles expressed by the previously described [D'Urso CM et al (1992) J Clin Invest 87: 284-292] beta2m-defective human melanoma FO-1 cell line and tested their ability to interact with calnexin, calreticulin and the TAP (transporter associated with antigen processing) complex. All these alleles were found to bind calnexin, but not calreticulin or the poorly expressed TAP complex, both in parental and beta2m-transfected FO-1 cells, demonstrating a complex defect of class I expression in FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more strongly than A25 and B8, and preferentially accumulated in the endoplasmic reticulum, in both a calnexin-associated and a calnexin-free form. In addition, they could be transported to the cell surface at low levels even in the absence of beta2m, without undergoing terminal glycosylation. These results establish a parallel between HLA-C and the murine Db and Ld molecules which have been found to be surface expressed and functional in beta2m-defective cells. They also demonstrate distinctive features of HLA-C molecules. We propose that the accumulation of several assembly intermediates of HLA-C might favour the binding of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic cells with suboptimal class I expression. (+info)
Serum hyaluronan in patients with multiple myeloma: correlation with survival and Ig concentration.
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Serum from 386 myeloma patients were analyzed for serum hyaluronan (HYA) at diagnosis. Median age was 68 years (range, 32 to 87 years). The distribution of Ig classes was typical (58% IgG, 21% IgA, 1% IgD, and 20% light chain disease). The patients comprised 58% in stage III, 33% in stage II, and 9% in stage I. The majority (82%) had HYA values within an intermediate range (10 to 120 micrograms/L), 13% had high values (>120 micrograms/L), and 5% had abnormally low values (0 to 9 micrograms/L). For the first time, a patient group with abnormally low HYA serum values is reported. An inverse correlation between survival and HYA serum level was found (P =.015). When tested separately, patients with abnormally low or high HYA values had significantly shorter median survival (21.1 and 19.7 months, respectively) than those with an intermediate HYA concentration (32. 6 months; P =.005). Patients with abnormally low or high HYA levels had more advanced disease as judged by staging and biochemical markers. Interestingly, there was an inverse correlation between the HYA value and the M-component concentration in serum. Fifty percent of patients with abnormally low HYA values had IgA myelomas. In conclusion, the serum concentration of HYA may be of prognostic value in selected cases of multiple myeloma. Further studies will be performed to elucidate possible explanations for our findings, especially those related to the HYA cell surface binding proteins. (+info)
Use of major histocompatibility complex class I/peptide/beta2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys.
(30/1648)
To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8(+) CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8(+) CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/beta2m complexes. All SHIV-infected Mamu-A*01(+) rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8(+) CTL response is dominant and the p41A- and p68A-specific CD8(+) CTL responses are nondominant. These results indicate that CD8(+) CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8(+) CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach. (+info)
Crystal structure of the MHC class I homolog MIC-A, a gammadelta T cell ligand.
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The major histocompatibility complex (MHC) class I homolog MIC-A functions as a stress-inducible antigen that is recognized by a subset of gammadelta T cells independent of beta2-microglobulin and bound peptides. Its crystal structure reveals a dramatically altered MHC class I fold, both in detail and overall domain organization. The only remnant of a peptide-binding groove is a small cavity formed as the result of disordering a large section of one of the groove-defining helices. Loss of beta2-microglobulin binding is due to a restructuring of the interaction interfaces. Structural mapping of sequence variation suggests potential receptor binding sites on the underside of the platform on the side opposite of the surface recognized by alphabeta T cell receptors on MHC class I-peptide complexes. (+info)
An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals.
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We describe here a new subset of T cells, found in humans, mice, and cattle. These cells bear a canonical T cell receptor (TCR) alpha chain containing hAV7S2 and AJ33 in humans and the homologous AV19-AJ33 in mice and cattle with a CDR3 of constant length. These T cells are CD4(-)CD8(-) double-negative (DN) T cells in the three species and also CD8alphaalpha in humans. In humans, their frequency was approximately 1/10 in DN, 1/50 in CD8alpha+, and 1/6,000 in CD4(+) lymphocytes, and they display an activated/memory phenotype (CD45RAloCD45RO+). They preferentially use hBV2S1 and hBV13 segments and have an oligoclonal Vbeta repertoire suggesting peripheral expansions. These cells were present in major histocompatibility complex (MHC) class II- and transporter associated with antigen processing (TAP)-deficient humans and mice and also in classical MHC class I- and CD1-deficient mice but were absent from beta2-microglobulin-deficient mice, indicating their probable selection by a nonclassical MHC class Ib molecule distinct from CD1. The conservation between mammalian species, the abundance, and the unique selection pattern suggest an important role for cells using this novel canonical TCR alpha chain. (+info)