The effect of corticosteroids and other antineoplastic agents on the generation of leukocyte migration inhibition factor

We have shown that hydrocortisone in physiological concentrations can inhibit the production of leukocyte migration inhibition factor (LMIF), but does not diminish the action of this lymphokine. Other agents tested failed to influence LMIF production. Inhibition of LMIF production by corticosteroids was influenced by the nature of the stimulus used for the production as an effect could be seen with PHA or Con A, but not Staphylococcal enterotoxin A (SEA). Production of LMIF was promptly restored after removal of the steroids. Furthermore, addition of a calcium ionophore to PHA restored the production of LMIF even in the presence of corticosteroids. In contrast, addition of exogenous IL-2 did not correct the defect in lymphokine secretion. We believe that inhibition of the production of LMIF by steroid may lead to defective granulocytic function and thus, predispose to infection.     

A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington's disease

We compared four diagnostic data sets for the assessment of individuals at risk for Huntington's disease. Fifty-four chorea-free persons were evaluated by neurological examination, positron emission tomography measurement of glucose metabolism, radiographic computerized tomographic measurement of caudate size, and genetic testing at the polymorphic DNA loci D4S10, D4S43, and D4S125. Twelve (22%) persons had abnormal caudate metabolism, 6 (11%) had subtle abnormalities of motor control, and 7 (13%) had computed tomographic evidence of caudate atrophy, compared with an expected gene frequency of 34% for this population. In 20 persons with unambiguous genetic test results or the subsequent phenotypic expression of Huntington's disease (chorea), there was a greater sensitivity of the positron emission tomographic measurement of caudate metabolism (75%) relative to computed tomography (33%) or the clinical examination (17%) for the determination of a subpopulation of probable Huntington's disease gene carriers. Hypometabolism of the putamen and globus pallidus, and hypermetabolism of the precentral gyrus were also associated with a high probability of carrying the Huntington's disease gene. The findings support the hypothesis that abnormalities of cerebral metabolism precede clinical or structural (computed tomographic) abnormalities in gene-positive individuals at risk for Huntington's disease.     

Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.     

Acute effects of dialysis on T lymphocytes in patients with end-stage renal disease

The acute effect of dialysis on T-lymphocyte responses was studied in 11 patients with end-stage renal disease (ESRD). The in-vitro mitogenic response to concanavalin A and pokeweed mitogen was decreased (p less than 0.05) after single passage of blood through the dialyzer, accompanied by a reduction in the proportion of monoclonal antibody-defined total T lymphocytes (Leu 1+ cells) (p less than 0.01), an increase in the percentage of monoclonal antibody-defined monocytes (M 2+ cells), and a decrease in interleukin 2 (IL-2) production (p less than 0.05). Depletion of adherent cells from mononuclear cells isolated from blood after single passage through the dialyzer restored the mitogenic responses to normal levels. Post dialysis mitogenic responses were comparable to pre-dialysis mitogenic responses although IL-2 production (p less than 0.05), and the proportion of T lymphocyte (Leu 1+ cells) remained depressed (p less than 0.01). Cumulative effects of long-term intermittent hemodialysis may contribute to the impaired immunity and the increased frequency of infections and neoplasms in patients with end-stage renal disease.     

Examination of Association with Candidate Genes for Diabetic Nephropathy in a Mexican American Population

Background and objectives: Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups. CNDP1 and ELMO1 were examined along with eight other genes that are less well characterized for DN in a new study of Mexican-Americans.Design, setting, participants, & measurements: The target sample was patients of Mexican-American ancestry collected from three centers: 455 patients with DN and 437 controls with long-term diabetes but no incident nephropathy. Forty-two, 227, and 401 single nucleotide polymorphisms (SNPs) in CNDP1, ELMO1, and the other eight genes, respectively, were examined.Results: No region in CNDP1 or ELMO1 showed significant P values. Of the other eight candidate genes, an association of DN with a SNP pair, rs2146098 and rs6659783, was found in hemicentin 1 (HMCN1) (unadjusted P = 6.1 × 10⁻⁵). Association with a rare haplotype in this region was subsequently identified.Conclusions: The associations in CNDP1 or ELMO1 were not replicable; however, an association of DN with HMCN1 was found. Additional work at this and other loci will enable refinement of the genetic hypotheses regarding DN in the Mexican-American population to find therapies for this debilitating disease.Diabetic nephropathy (DN) is the main cause of ESRD in the United States (1). The disease burden in people of Mexican-American descent is particularly high (1), but there are only a limited number of studies that have characterized genes for DN in this ethnic group. Recently, two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1), were reported to be associated with DN (2–5). Janssen et al. (4) reported an association between DN and a microsatellite marker, D18S880, in CNDP1 among type 1 and type 2 diabetic patients from four different countries, and Freedman et al. (2) reported its replication among type 2 diabetic Caucasian patients. Shimazaki et al. (5) reported an association in the Japanese population between DN and ELMO1, which includes rs741301 as the most significant single nucleotide polymorphism (SNP).Here, we study ten candidate genes for their association with DN in the Mexican-American population. We attempt to replicate the previous associations of CNDP1 and ELMO1 with a sample size that is similar or greater than previously used (2–5). In addition, we study the following eight genes, which are good biologic candidates but have not been studied extensively: hemicentin 1 (HMCN1), complement factor H (CFH), α-2Heremans-Schmid-glycoprotein (AHSG), caspase 3 (CASP3), heat shock 70-kD protein 1A (HSPA1A), heat shock 27-kD protein 1 (HSPB1), caspase 12 (CASP12), and heme oxygenase (decycling) 1 (HMOX1).HMCN1 was shown to be associated with change in calculated GFR (6), but its role in DN has never been examined. CFH is long known to play a role in atypical hemolytic uremia and membranoproliferative GN, but its involvement in DN has not been evaluated. AHSG is reported to be associated with type 2 diabetes and dyslipidemia, it inhibits insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (7), and it has been identified as a marker of acute kidney injury (8). Its serum concentration is increased in nondialyzed patients with DN (9) and is low in patients with ESRD (10). High serum levels are associated with insulin resistance (11). HSPB1, also known as HSP27, is involved in the regulation of cell adhesion and invasion (12), regulates actin cytoskeleton turnover, and has anti-apoptotic and antioxidant properties in a wide variety of cells and tissues (13). A mutation in HSPB1 causing a variant of Charcot-Marie-Tooth disease is associated with the development of focal and segmental glomerulosclerosis (14). HMOX1, also known as HO-1, provides antioxidant adaptive functions in response to renal injury (15) and is associated with the degree of renal failure in DN (16). CASP3 and CASP12 mediate apoptotic cell death and were chosen as candidate genes because of their relevance to DN (17,18). Finally, HSPA1A was chosen because of its cellular protectant role in the unfolded protein response (19).Our study aimed to replicate the previous association of the two genes with DN and/or discover new associations at the other eight genes of biologic importance by contrasting the genotype frequencies of SNPs in these ten genes between cases and controls after allowing for relevant covariates.     

Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND)

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.