PubMed Health⌕ Search

Biomedical subjects

P L Podolin

Publications and source records attributed to P L Podolin.

17 recordsLinked to original sources
PubMed2000

Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene?

The insulin-dependent diabetes (Idd) gene, Idd3, has been localised to a 0.35 cM region of chromosome 3 containing the structural gene for the cytokine interleukin 2 (IL-2). While variation of the N-terminal amino acid sequence of IL-2 has been shown to correlate with Idd3 allelic variation, differences in induction of proliferation by IL-2 allotypes have not been detected. In the current study, we examined the electrophoretic migration of IL-2 allotypes and have found two distinct patterns, consistent with differences in glycosylation, that correlate with diabetes-resistance and susceptibility. These findings strongly suggest that IL-2 variants may be functionally distinct.

Alleles↗
PubMed2000

Inhibition of contact sensitivity in human CD4+ transgenic mice by human CD4-specific monoclonal antibodies: CD4+ T-cell depletion is not required.

Clenoliximab and keliximab are monkey/human chimeric monoclonal antibodies (mAbs) of the immunoglobulin G4 (IgG4) and IgG1 isotypes, respectively, that recognize the same epitope on human CD4. The two mAbs possess identical idiotypes and exhibit equal affinities for CD4. Upon administration of these mAbs to mice that express a human CD4 transgene, but not mouse CD4 (HuCD4/Tg mice), clenoliximab and keliximab exhibited similar kinetics of binding to CD4, and induced the same degree of CD4 modulation from the cell surface, although only keliximab mediated CD4+ T-cell depletion. Epicutaneous sensitization and challenge of HuCD4/Tg mice with the hapten oxazolone resulted in a contact sensitivity response characterized by tissue swelling, and the presence of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in the local tissue. Administration of a single 2-mg dose of either clenoliximab or keliximab to HuCD4/Tg mice prior to sensitization significantly reduced post-challenge tissue swelling, and levels of IFN-gamma and IL-4, indicating that CD4+ T-cell depletion is not required for anti-CD4 mAb-mediated inhibition of contact sensitivity. Administration of either mAb prior to challenge failed to inhibit the contact sensitivity response, indicating differential sensitivity of the afferent and efferent phases of the response to inhibition by CD4-specific mAbs. Collectively, these data indicate that CD4 functions as a positive regulatory molecule in the contact sensitivity response.

Adjuvants, Immunologic↗
PubMed2000

Modulation of human monocyte activities by tranilast, SB 252218, a compound demonstrating efficacy in restenosis.

Tranilast (SB 252218) is a compound initially identified as an anti-atopic agent. Recently the compound has demonstrated clear beneficial effects in animal models of restenosis. Here we confirm tranilast has broad and profound effects on human monocytes, which could contribute to the vascular antifibrotic activity. Tranilast exhibited significant immunomodulatory activity inhibiting endotoxin-induced prostaglandin E(2) (PGE(2); IC(50) = approximately 1-20 microM), thromboxane B(2) (IC(50) = approximately 10-50 microM), transforming growth factor-beta1 (TGF-beta1; IC(50) = approximately 100-200 microM), and interleukin-8 (IC(50) = approximately 100 microM) formation, but had no effect on tumor necrosis factor-alpha. Interleukin-12 and -18-induced interferon-gamma formation by monocytes was also attenuated by tranilast. A23187-induced monocyte leukotriene C(4) or PGE(2) formation was inhibited by tranilast at IC(50) values of 10-40 microM and 2-20 microM, respectively, incubated with or without exogenous arachidonic acid. Interestingly, tranilast (up to 1000 microM) had no direct effects on cyclooxygenase I or II activity, nor did it have significant effects on human type IIA 14 kDa or type IV 85 kDa phospholipase A(2) activity. Furthermore, tranilast had no effect on endotoxin-induced cyclooxygenase II protein expression, suggesting tranilast modulates eicosanoid production and release by an as yet unidentified mechanism. Alternatively, the expression of TGF-beta1 was inhibited by tranilast but found to be due in part to inhibition of PGE(2) because exogenous PGE(2) could abrogate tranilast-mediated inhibition of TGF-beta1. Taken together, although a reported direct inhibitor of fibroblast proliferation, we show tranilast also attenuates the proinflammatory activity of human monocytes, adding to its potential efficacy as a therapeutic agent in restenosis.

Arachidonic Acid↗
PubMed1998

Localization of two insulin-dependent diabetes (Idd) genes to the Idd10 region on mouse chromosome 3.

Multiple genes control the development of autoimmune diabetes both in humans and in the nonobese diabetic (NOD) strain of mouse. Previously, three insulin-dependent diabetes (Idd) genes, Idd3, Idd10, and Idd17, were localized to mouse Chromosome (Chr) 3. The B10- or B6-derived resistance alleles at Idd10 and Idd3 together provide the NOD mouse with nearly complete protection from diabetes. In the present study, the 10.2-cM region encoding Idd10 was defined further with newly developed congenic strains. A locus, located in the centromeric 2.1 cM of the 10.2 cM region, contributed to the Idd10 trait. However, this locus did not account for the full effect of Idd10, suggesting the presence of a second gene in the distal portion of the 10.2-cM region. This second gene is designated as Idd18 and is localized to a 5.1-cM region. The resolution of the originally defined Idd3 locus into at least four separate loci, Idd3, Idd10, Idd17, and Idd18, illustrates the complex polygenic nature of diabetes.

Animals↗
PubMed1997

Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1.

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple insulin-dependent diabetes (Idd) genes. The Idd3 gene, originally defined as a broad peak of linkage on mouse chromosome 3, was subsequently identified as two genes, Idd3 and Idd10, separated by at least 20 cM. The resistance alleles of Idd3 and Idd10 individually confer only partial protection from diabetes but, in combination, result in profound resistance to disease due to an epistatic genetic interaction. In this study, we used newly developed congenic strains to further localize Idd10. Surprisingly, we found that Idd10 itself comprises at least two linked loci: Idd10 and the newly designated Idd17. Idd17 was localized to a 1.1-cM region between D3Mit26 and D3Mit40, proximal to Fcgr1, a candidate gene encoding the high affinity Fc receptor for IgG. Idd10 was localized to a 10-cM region between D3Mit213 and D3Mit106, distal to Fcgr1. Thus, Fcgr1 was excluded as a candidate for either Idd10 or Idd17, despite the fact that the NOD strain expresses a mutant form of the receptor. Interestingly, although Idd10 and Idd17 participate in a genetic interaction with each other, Idd10 but not Idd17 participates in the genetic interaction with Idd3. Our study on chromosome 3 begins to reveal the extent of the polygenic nature of autoimmune diabetes, and demonstrates that the use of congenic strains is an effective mapping strategy, even in the dissection of multiple, linked genes with subtle effects.

Alleles↗
PubMed1997

Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene.

Currently, 16 loci that contribute to the development of IDDM in the NOD mouse have been mapped by linkage analysis. To fine map these loci, we used congenic mapping. Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene. Segregation analysis of the known variations within this interval indicated that only one variant, a serine-to-proline substitution at position 6 of the mature interleukin-2 (IL-2) protein, consistently segregates with IDDM in crosses between NOD and a series of nondiabetic mouse strains. These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium.

Amino Acid Sequence↗
PubMed1994

Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes.

Development of diabetes in NOD mice is polygenic and dependent on both major histocompatibility complex (MHC)-linked and non-MHC-linked insulin-dependent diabetes (Idd) genes. In (F1 x NOD) backcross analyses using the B10.H-2g7 or B6.PL-Thy1a strains as the outcross partner, we previously identified several non-MHC Idd loci, including two located on chromosome 3 (Idd3 and Idd10). In the current study, we report that protection from diabetes is observed in NOD congenic strains having B6.PL-Thy1a- or B10-derived alleles at Idd3 or Idd10. It is important to note that only partial protection is provided by two doses of the resistance allele at either Idd3 or Idd10. However, nearly complete protection from diabetes is achieved when resistance alleles are expressed at both loci. Development of these congenic strains has allowed Idd3 to be localized between Glut2 and D3Mit6, close to the Il2 locus.

Alleles↗
PubMed1994

Ultraviolet regulation of neuroendocrine and circadian physiology in rodents.

UV wavelengths can regulate neuroendocrine and circadian responses in some rodent species. Appropriately timed UV exposures can block the short photoperiod-induced collapse of the reproductive system, cause a rapid suppression of nocturnal melatonin synthesis, regulate melatonin rhythms and phase shift wheel running rhythms. These biological effects of UV are not dependent on the Harderian gland or melanin in the eye, but appear to be related to the degree of transmission through the ocular lens. Such results are consistent with the hypothesis that elements in the retina can transduce UV stimuli for circadian and neuroendocrine regulation.

Albinism↗
PubMed1994

Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes.

The role of CD8+ T-cells in the development of diabetes in the nonobese diabetic (NOD) mouse remains controversial. Although it is widely agreed that class II-restricted CD4+ T-cells are essential for the development of diabetes in the NOD model, some studies have suggested that CD8+ T-cells are not required for beta-cell destruction. To assess the contribution of CD8+ T-cells to diabetes, we have developed a class of NOD mouse that lacks expression of beta 2-microglobulin (NOD-B2mnull). NOD-B2mnull mice, which lack both class I expression and CD8+ T-cells in the periphery, not only failed to develop diabetes but were completely devoid of insulitis. These results demonstrate an essential role for CD8+ T-cells in the initiation of the autoimmune response to beta-cells in the NOD mouse.

Animals↗
PubMed1993

I-E+ nonobese diabetic mice develop insulitis and diabetes.

The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.

Animals↗
PubMed1993

Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice.

A congenic, non-obese diabetic (NOD) mouse strain that contains a segment of chromosome 3 from the diabetes-resistant mouse strain B6.PL-Thy-1a was less susceptible to diabetes than NOD mice. A fully penetrant immunological defect also mapped to this segment, which encodes the high-affinity Fc receptor for immunoglobulin G (IgG), Fc gamma RI. The NOD Fcgr1 allele, which results in a deletion of the cytoplasmic tail, caused a 73 percent reduction in the turnover of cell surface receptor-antibody complexes. The development of congenic strains and the characterization of Mendelian traits that are specific to the disease phenotype demonstrate the feasibility of dissecting the pathophysiology of complex, non-Mendelian diseases.

Animals↗
PubMed1991

The kinetics of vimentin RNA and protein expression in interleukin 2-stimulated T lymphocytes.

In this paper, we examine the regulation of vimentin expression during interleukin 2-induced proliferation of the cloned helper T cell line, L2. We observe a 10-20-fold increase in steady-state vimentin RNA that is accompanied by a 14-fold increase in the rate of vimentin protein synthesis. This indicates that translation is occurring, and thus that vimentin expression is regulated, at least in part, at the level of transcription and/or RNA stability, rather than at the level of protein synthesis. In contrast to the increases in steady-state vimentin RNA and the rate of protein synthesis, steady-state vimentin protein levels increase maximally only 1.3-3-fold in proliferating L2 cells. The rate of vimentin protein turnover remains relatively constant throughout L2 cell activation, active proliferation, and return to quiescence, indicating that an increased rate of turnover does not account for the minimal increase in vimentin content. These observations are consistent with a transient increase in vimentin protein synthesis necessary to support L2 cell growth and/or vimentin network reorganization. Because cell division occurs before an equilibrium state is reached, the maximal increase in steady-state vimentin protein content is never attained.

Blood Proteins↗
PubMed1990

cDNA cloning and characterization of interleukin 2-induced genes in a cloned T helper lymphocyte.

Clonal expansion of antigen-specific lymphocytes is an important aspect of the immune response. Interleukin 2 (IL2) is largely responsible for the amplification of antigen-specific T cells. In this study, the changes in gene expression accompanying interleukin 2 stimulation of T cells are examined, using a cloned T helper lymphocyte line as a model system. To isolate cDNA clones of IL2-induced genes, a cDNA library was screened by differential hybridization. Twenty-one different cDNA clones were isolated by this method, comprising six glycolytic enzymes, vimentin, alpha-tubulin, beta-actin, gamma-actin, ERp99, elongation factor 2, ribosomal phosphoprotein P1, the DNA-binding protein dbpB/YB-1, as well as seven clones which do not correspond to any previously described sequences. These clones are used to study the time course of expression and the sensitivity to cycloheximide inhibition of IL2-induced mRNAs. In addition, the tissue specificity of the unidentified mRNAs is examined, and two of these are shown to be expressed at high levels in normal mouse brain, with much lower or undetectable levels in the other tissues tested. These cDNA clones will be useful in future studies to determine the molecular basis of IL2-induced gene expression.

Animals↗
PubMed1987

Neuroimmunology: modulation of the hamster immune system by photoperiod.

Groups of adult male Syrian hamsters were kept in a long photoperiod (LD 14:10) or a short photoperiod (LD 10:14). After 12 weeks, half of the animals in each light:dark cycle were immunized with an immunogenic amino acid polymer. Exposure to short photoperiod was associated with a significant reduction in testicular, accessory sex organ, splenic and brown fat weights. However, photoperiod length did not influence whole body, thymic, adrenal or kidney weights. Spleens of immunized animals in the long photoperiod were significantly heavier than those of unimmunized animals in the long photoperiod, and both were heavier than spleens from immunized or unimmuized animals in the short photoperiod. This reflected increased splenic lymphocyte and macrophage counts. However, there was no difference in antibody production between animals kept in different photoperiods. These results demonstrate that the daily photoperiod length affects both hamster reproductive competence as well as selected immune parameters (splenic weight and mononuclear cell hyperplasia) but does not alter antibody production.

Adipose Tissue, Brown↗
PubMed1987

The suppression of nocturnal pineal melatonin in the Syrian hamster: dose-response curves at 500 and 360 nm.

It has recently been shown that wavelengths in the near-UV range (UV-A, 320-400 nm) are capable of influencing pineal melatonin content in the hamster. The purpose of this study was to compare the capacities of monochromatic visible and UV radiation for suppressing nocturnal pineal melatonin. Groups of male Syrian hamsters adapted to a 14-h light, 10-h dark cycle (lights on, 1700-0700 h) were exposed to irradiances of 500 or 360 nm light for 5 min during their dark phase. Both wavelengths suppressed pineal melatonin in a dose-related manner. The resultant fluence-response curves were similar in shape, although their corresponding threshold irradiances were markedly different. The calculated ED50 values for 500 and 360 nm light were 0.022 microW/cm2 (1.66 X 10(13) photons/cm2) and 0.306 microW/cm2 (1.66 X 10(14) photons/cm2), respectively. These data show that the induction of a 50% depression of pineal melatonin requires 10 times the number of 360-nm photons compared to 500-nm photons at the level of the cornea. Despite this difference in sensitivity to wavelength, environmental irradiances of UV-A are well above the threshold for melatonin suppression in the hamster. These results thus demonstrate the importance of considering UV-A, in addition to the visible wavelengths, in the regulation of hamster pineal physiology.

Animals↗
PubMed1986

Near-ultraviolet radiation suppresses pineal melatonin content.

UV radiation (200-400 nm) is generally considered to be outside the range of visible illumination for mammals. The aim of this study was to determine if UV wavelengths can influence pineal physiology. Experiments on hamsters confirm that wavelengths as low as 305 nm are transmitted through the clear ocular media to the retina. Furthermore, low irradiances of broadband (340-405 nm) and monochromatic (360 nm) UV radiation are capable of suppressing high nocturnal levels of pineal melatonin in intact, but not blind, hamsters. These data indicate that the hamster eye and neuroendocrine system are able to detect and respond to near-UV wavelengths.

Animals↗