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Biomedical subjects

D J Mitchell

Publications and source records attributed to D J Mitchell.

At least 55 records · Page 3Linked to original sources
PubMed1989

Pseudotumor cerebri and macular disease.

The most common indications for treatment of patients with pseudotumor cerebri are the presence of severe intractable headaches and evidence of optic neuropathy. The role of the ophthalmologist in following patients with pseudotumor cerebri has been to document optic nerve dysfunction in terms of visual field abnormalities or loss of visual acuity. Macular changes have been described in association with papilledema. A case of pseudotumor cerebri and associated macular disease is reviewed to call attention to the need for the ophthalmologist to differentiate between visual loss secondary to optic neuropathy from that of macular disease. The case illustrates how quickly macular disease can develop. The management of patients with pseudotumor cerebri is discussed.

Adult↗
PubMed1988

Multiple discrete encephalitogenic epitopes of the autoantigen myelin basic protein include a determinant for I-E class II-restricted T cells.

Immunization with the autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE). Initial investigations indicated that encephalitogenic murine determinants of MBP were located only within MBP 1-37 and MBP 89-169. Encephalitogenic T cell epitopes within these fragments have been identified. Each epitope is recognized by T cells in association with separate allelic I-A molecules. A hybrid I-E-restricted T cell clone that recognizes intact mouse (self) MBP has been examined. The epitope recognized by this clone includes MBP residues 35-47. When tested in vivo, p35-47 causes EAE. T cell recognition of p35-47 occurs only in association with I-E molecules. These results provide the first clear example that antigen-specific T cells restricted by I-E class II molecules participate in murine autoimmune disease. Furthermore, it is clear that there are multiple (at least three) discrete encephalitogenic T cell epitopes of this autoantigen, each recognized in association with separate allelic class II molecules. These results may be relevant to human autoimmune diseases whose susceptibility is associated with more than one HLA-D molecule.

Amino Acid Sequence↗
PubMed1988

Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention.

Experimental allergic encephalomyelitis (EAE) is an induced autoimmune disease mediated by CD4+ T lymphocytes. Analysis of T cell receptors of myelin basic protein-specific encephalitogenic T cell clones derived from six different PL/J (H-2u) or (PL/J x SJL) F1 (H-2uxs) mice revealed a limited heterogeneity in primary structure. In vivo, the majority of T lymphocytes recognize the N-terminal MBP-nonapeptide in association with I-Au and utilize the V beta 8 gene element. cDNA-sequencing showed that all T cell receptors from a panel of such T cell clones, grown in vitro, share the same V alpha gene segment. Despite heterogeneity in the D-J regions, the clones unexpectedly display a striking similarity in fine specificity. Based on these results, prevention and reversal of autoimmune disease with V beta 8-specific monoclonal antibodies was achieved.

Amino Acid Sequence↗
PubMed1988

Predominant expression of a T cell receptor V beta gene subfamily in autoimmune encephalomyelitis.

TCR beta chain gene expression of individual T cell clones that share the same MHC class II restriction and similar fine specificity for the encephalitogenic NH2 terminus of the autoantigen myelin basic protein (MBP) has been examined. TCR V beta expression was examined by FACS analysis with mAbs specific for the V beta 8 subfamily of TCR beta chain genes. 14 of 18 (78%) NH2-terminal MBP-specific clones examined express a member of the TCR V beta 8 subfamily. Southern analysis was used to identify which member(s) of the TCR V beta 8 subfamily is expressed by these clones. Each of four clones examined uses V beta 8.2, though two different V beta 8.2-J beta 2 combinations were identified. Our findings indicate that there is restricted TCR V beta usage in the autoimmune T cell response to the dominant encephalitogenic NH2-terminal epitope of the MBP. The use of an mAb to the antigen-specific TCR in the prevention of T cell-mediated autoimmune disease has been investigated. Our results demonstrate that in vivo administration of a TCR V beta 8-specific mAb prevents induction of autoimmune encephalomyelitis.

Animals↗
PubMed1988

Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein.

The C-terminal 89-169 amino acid fragment of myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE) in SJL/J mice. In order to identify the encephalitogenic T cell epitope, we have examined the fine specificity of encephalitogenic SJL/J T cell clones with synthetic peptides derived from the C-terminal 89-169 amino acids of MBP. These peptides were examined for their immunogenic and encephalitogenic activity in the SJL/J mouse. The SJL/J-derived, encephalitogenic T cell clone, 4b.14a, was shown to be responsive to rat myelin basic protein synthetic peptides pR89-101 (VHFFKNIVTPRTP) as well as to intact MBP. Its response was effectively blocked by mAb 10-2.16 (anti-I-As) as was the response to intact MBP. Furthermore, pR89-101 was revealed to be highly immunogenic for the (PLSJ)F1 mouse in terms of lymphocyte proliferation, but not for the PL/J mouse, in spite of the fact that there exists a strong bias to H-2u restricted responses in the (PLSJ)F1 mouse at the T cell level. By using pR89-101, T cells of (PLSJ)F1 origin were revealed to recognize the peptide in association with the I-As molecule on (PLSJ)F1 antigen presenting cells (APC). When examined for encephalitogenicity for the SJL/J mouse, pR89-101 was found to be as encephalitogenic as intact rat MBP. These results demonstrated that MBP peptide pR89-101 is a major encephalitogenic determinant for the SJL/J mouse.

Amino Acid Sequence↗
PubMed1988

Successful treatment of EAE in rhesus monkeys with MHC class II specific monoclonal antibodies.

Experimental Allergic Encephalomyelitis (EAE) was induced in rhesus monkeys by subcutaneous immunization with calfbrain homogenate in complete Freunds adjuvant. Monkeys were treated with major histocompatibility complex (MHC) Class II specific monoclonal antibodies (MoAb) as soon as the first clinical EAE signs became apparent. Two different treatments were tested. One consisted of 10 daily injections of a mixture of two MHC Class II specific MoAb, reactive with a monomorphic structure of rhesus monkey Class II molecules. The other consisted of 10 daily injections of Genox3.53, specific for HLA-DQW1. This MoAb crossreacts well with monkeys and also detects a polymorphism in this species and is presumably reactive with the RhLA-DQW1 antigen. Both MoAb treatments could modify the clinical course of EAE favourably. Untreated animals invariably died within 3 d of the onset of clinical EAE signs. Only one of the three monkeys treated with the monomorphic MHC Class II MoAb preparation died within 3 d, and the other two survived significantly longer than untreated animals. Both animals treated with Genox3.53 survived significantly longer than untreated control animals. Although only a few animals were tested, these results clearly show the possible beneficial influence of MHC Class II specific MoAb on a T-cell mediated autoimmune disease.

Animals↗
PubMed1988

The attractive forces between polar lipid bilayers.

Long-range attractive forces between lipid bilayers are not well described by the Lifshitz theory of Van der Waals forces between macroscopic media. It is shown that when correlations between polar headgroups are taken into account, the predicted forces take a qualitatively different form consistent with the measured data.

Biophysical Phenomena↗
PubMed1988

Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein.

The peptide p89-101 (Val-His-Phe-Phe-Lys-Asn-Ile-Val-Thr-Pro-Arg-Thr-Pro) of myelin basic protein is encephalitogenic in mice expressing H-2q and H-2s antigens. Six of 13 encephalitogen-specific T-cell clones were shown to express the variable beta-chain (V beta) 17a gene product (KJ23a+), whereas seven clones were KJ23a-. Both KJ23a+ and KJ23a- subpopulations were encephalitogenic in SJL/J mice when adoptively transferred. Depletion of KJ23a+ cells in vivo with the administration of the antibody KJ23a suppresses experimental allergic encephalomyelitis induced with KJ23a+ T-cell lines. However, experimental allergic encephalomyelitis induced with either (i) encephalitogenic peptide p89-101, (ii) intact myelin basic protein, or (iii) KJ23a- T cells reactive to p89-101 cannot be prevented with monoclonal antibody KJ23a. These data indicate that in spite of the V beta 17a gene expression in a relatively large proportion of p89-101-specific T cells, such V beta gene use is not essential for the induction of experimental allergic encephalomyelitis in SJL/J mice. These results contrast with the predominance of V beta gene use (V beta 8.2) in T cells reactive to the encephalitogenic fragment (pR1-11) in PL/J mice. One reason for this lack of dominant use of a particular T-cell receptor V beta gene family in the autoimmune response to myelin basic protein in SJL/J mice stems from the observation that two encephalitogenic epitopes exist in p89-101. KJ23a- T cells are stimulated by the deleted peptide p89-100, whereas KJ23a+ T cells are not. Thus, in the response to an encephalitogenic fragment of myelin basic protein containing two nested epitopes, at least two distinct T-cell receptor V beta genes are expressed. These distinct T-cell subpopulations can each trigger experimental allergic encephalomyelitis. These findings have implications for therapy of autoimmune disease with antibodies to the T-cell receptor gene products.

Animals↗
PubMed1988

Can the accuracy of intraocular lens calculations be improved?

Regression analysis of data from 222 extracapsular cataract extractions was performed to determine if the accuracy of IOL prediction in cataract surgery can be improved. Polynomial and piecewise regression of large, medium, and short eyes were used to calculate new formulas for IOL prediction. The Taylor series representation of the theoretical lens power formula was calculated to determine what combination of the variables for IOL power prediction are reasonable to consider in constructing a polynomial regression model. The formulas calculated from the data in this study were compared with other published methods of IOL calculation. In this study, the difference between the postoperative refraction error and emmetropia was independent of the formula used. The exception was the modified Binkhorst formula, which caused greater error. Inclusion of higher order terms in the regression formula or piecewise regression did not reduce the postoperative refractive error.

Evaluation Studies as Topic↗
PubMed1987

T cell specificity for class II (I-A) and the encephalitogenic N-terminal epitope of the autoantigen myelin basic protein.

The role of class II restriction in T cell recognition of an epitope of the autoantigen myelin basic protein (MBP) has been investigated. Encephalitogenic PL/J(H-2u) and (PL/J X SJL/J(H-2s))F1 ((PLSJ)F1) clones, isolated after immunization with intact MBP, recognize the N-terminal 11 amino acid residues of MBP in association with I-Au class II molecules. The synthetic peptide MBP 1-11 has been tested in vivo for induction of EAE. Clinical and histological EAE occurs in PL/J and (PLSJ)F1 mice but not SJL/J. The class II restriction of T cells primed with MBP 1-11 has been examined in primary cultures in vitro. Similar to encephalitogenic T cell clones, isolated after continuous selection in vitro, the population of MBP 1-11-specific proliferative PL/J and (PLSJ)F1 T cells, recognize this epitope in association with I-Au class II molecules. Not all MBP-specific T cell clones which are restricted to I-Au class II molecules cause autoimmune encephalomyelitis. The specificity of these non-encephalitogenic clones has been examined in this report. These clones also recognize MBP 1-11. Thus recognition of an encephalitogenic T cell epitope is not sufficient for induction of EAE.

Animals↗
PubMed1987

Gene-protein assignments within the yeast Yarrowia lipolytica dsRNA viral genome.

Some strains of the yeast Yarrowia lipolytica possess virus-like particles (VLPs) which encapsidate a double-stranded RNA (dsRNA) genome designated Ly. We report here that these VLPs have two associated polypeptides of molecular weights 83 kd (VLy-P1) and 77 kd (VLy-P2). Denatured Ly-dsRNA was used to program a cell-free rabbit reticulocyte translation system, resulting in the appearance of four major products, viz. Ly-P1 (83 kd); Ly-P2 (77 kd); Ly-P3 (74 kd) and Ly-P4 (68 kd). The in vivo viral-associated protein VLy-P1 co-migrated on SDS-polyacrylamide gels with the in vitro product Ly-P1 and, similarly, VLy-P2 co-migrated with Ly-P2. Peptide mapping data confirm the identity of the in vivo products (VLy-P1 and VLy-P2) and their in vitro counterparts. The conclusion made is that VLy-P1 and VLy-P2 are almost identical primary translation products of the Ly genome, derived from a single or multiple species of Ly-dsRNA. RNA blot hybridizations using L1A M1 and separately, L2A M2 probes prepared from appropriate K1 and K2 Saccharomyces cerevisiae killer strains, failed to show any detectable homology to Ly-dsRNA, substantiating the uniqueness of the Ly genome with respect to the K1 and K2 S. cerevisiae dsRNA killer systems.

Animals↗
PubMed1987

Cloning and genetic organization of the pca gene cluster from Acinetobacter calcoaceticus.

The beta-ketoadipate pathway of Acinetobacter calcoaceticus comprises two parallel metabolic branches. One branch, mediated by six enzymes encoded by the cat genes, converts catechol to succinate and acetyl coenzyme A (acetyl-CoA); the other branch, catalyzed by products of the pca genes, converts protocatechuate to succinate and acetyl-CoA by six metabolic reactions analogous or identical to those of the catechol sequence. We used the expression plasmid pUC18 to construct expression libraries of DNA from an A. calcoaceticus mutant strain from which the cat genes had been deleted. Immunological screening with antiserum to the pcaE gene product, beta-ketoadipate:succinyl-CoA transferase I, resulted in the isolation of a cloned 11-kilobase-pair (kbp) fragment which inducibly expressed all six pca genes under control of the lac promoter on pUC18. The induced Escherichia coli cells formed the six pca gene products at levels 10- to 30-fold higher than found in fully induced A. calcoaceticus cultures, although protocatechuate 3,4-dioxygenase (the iron-containing product of the pcaA gene) from the recombinant strain possessed a relatively low turnover number. An E. coli culture expressing the cloned pca genes quantitatively converted protocatechuate to beta-ketoadipate; failure of the organism to metabolize the latter compound can be most readily ascribed to relatively low pool levels of succinyl-CoA, a required substrate for beta-ketoadipate:succinyl-CoA transferase, in E. coli. The gene order and direction of transcription were determined to be pcACBDFE by identification of enzymes expressed in subclones, by using natural transformation to identify subclones carrying DNA corresponding to dysfunctional alleles in mutant A. calcoaceticus strains, and by restriction mapping of both the 11-kbp fragment and derivatives of the 11-kbp fragment containing Tn5 in the pcaA, pcaB, pcaD, and pcaE genes. The fragment containing the pca gene hybridized strongly and specifically to a previously cloned fragment containing A. calcoaceticus cat genes.

Acinetobacter↗
PubMed1986

Effects of dietary fat on mammary development relative to age and hormones in BALB/c mice.

Earlier studies reported that mammary ducts grew faster if the 10% fat in the diet was composed of oils containing polyunsaturated fatty acids (corn oil: CO) compared to hydrogenated cottonseed oil (HCTO), which is devoid of such fatty acids. These experiments were primarily carried out in immature mice and left unanswered questions regarding the effects of dietary fats on more differentiated stages of mammary development. The use of transplanted ducts permitted the study of mammary growth rates in adult mice. If the diet was started when the animals were adults, there was no difference in the growth rate of those fed HCTO diet compared to those fed CO diet. However, when the diets were fed to immature mice, the mammary gland grew slower in mice fed the HCTO diet, confirming our earlier observations. The HCTO and CO diets caused no difference in the growth rate or morphology of fine ducts and alveoli that developed during pregnancy. Furthermore, no differences were seen in female mice following 6 weeks of progesterone administration begun at 3 weeks of age. Experiments that used male mice to examine the initial stages of mammary duct growth also showed that the effect of dietary fat was not observed when estrogen (E) or E and progesterone (P) were injected. In addition, there was no effect of dietary fat in ovariectomized 3-week-old females when any dose of E was administered from 0.01 to 1 microgram/day. Examination of the ovaries from mice fed either HCTO or CO diets from 3 to 9 weeks or 3 to 13 weeks of age showed that mice fed HCTO diet did not develop corpora lutea, while those fed CO diet had normal appearing ovaries. The HCTO diet inhibits normal maturation of the follicle and corpus luteum formation. We conclude that the effect of the dietary fat on the developing mouse is on the maturation of the ovary and subsequently on mammary growth.

Age Factors↗
PubMed1985

Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition.

Class II-restricted T cell clones specific for myelin basic protein (MBP) have been generated from PL/J and (PL/J X SJL/J)F1 [((PLSJ)F1] mice following sensitization to rat MBP. Of 17 T cell clones generated from (PLSJ)F1 mice, 5 are I-Au(A alpha uA beta u) restricted, one is restricted to I-As(A alpha sA beta s), 10 are restricted to hybrid I-A(u X s)F1 (A alpha sA beta u) determinants, and one clone is restricted to hybrid I-E(u X s) (E alpha uE beta s) molecules. Thus, of 16 I-A-restricted T cell clones generated from (PLSJ)F1 mice, only one is I-As-restricted, reflecting a lack of priming to MBP in association with I-As. T cell clones restricted to I-Au and to I-E (E alpha u E beta s) molecules recognize mouse (self) MBP. Furthermore, only the five T cell clones restricted to I-Au molecules recognize a determinant in common with mouse (self) MBP within the encephalitogenic N-terminal peptide. Three such I-Au restricted T cell clones, derived independently, cause paralysis in 100% of (PL/J X SJL/J)F1 mice tested. Acute, chronic unremitting, and chronic relapsing paralysis are all induced following injection of these clones. Administration of greater numbers of cloned T cells causes acute and fatal experimental allergic encephalomyelitis, while administration of lower numbers of cloned T cells is associated with chronic unremitting and relapsing paralysis. Paralysis induced with T cell clones shares many clinical, immunologic, and histologic aspects with human demyelinating diseases such as multiple sclerosis. Histopathology reveals perivascular lymphocytic infiltration, demyelination, and remyelination. These studies demonstrate the utility of T cell clones for analyzing the association between class II major histocompatibility complex molecules and disease susceptibility.

Animals↗
PubMed1985

Mammary tumors in feral mice lacking MuMTV DNA.

Two mammary tumors developed in feral mice treated with dimethylbenzanthracene. The tumors, livers, and spleens of these animals contained no MuMTV proviral DNA. Neither tumor had amplified or rearranged int-1 or int-2 loci. This demonstrates that mammary tumorigenesis can occur in mice in the absence of endogenous and exogenous MuMTV.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Virus-like particle capsid proteins encoded by different L double-stranded RNAs of Saccharomyces cerevisiae: their roles in maintenance of M double-stranded killer plasmids.

The plasmid determinants of killer phenotypes in type K1 and K2 killer yeast cells are the 1.9-kilobase (kb) M1 and 1.7-kb M2 double-stranded RNAs (dsRNAs), respectively. These are dependent for their maintenance and encapsidation, in Saccharomyces cerevisiae virus ScV-M1 or ScV-M2 virus-like particles, on the capsid provided by one of a group of moderately related 4.7-kb dsRNAs called LA. The L1A and L2A dsRNAs found in naturally isolated K1 and K2 killers encode 88-kilodalton VL1A-P1 and 86-kilodalton VL2A-P1 capsids, respectively. These are competent for encapsidating homologous LA dsRNAs as well as M dsRNAs. Most strains of S. cerevisiae, including killers, contain one of a second group of closely related 4.7-kb dsRNAs called LBC. These encode their own 82-kilodalton capsid protein, VLBC-P1, which, at least in strains containing only LBC, encapsidates homologous dsRNA in ScV-LBC virus-like particles. In a K1 killer strain containing both L1A and LBC, ScV-M1 particles contain only VL1A-P1. In such strains it is probable that each virus-like particle contains a single capsid type and that each L dsRNA is encapsidated by a homologous capsid.

Capsid↗