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Biomedical subjects

C M Parker

Publications and source records attributed to C M Parker.

At least 37 records · Page 2Linked to original sources
PubMed1997

Internal validity of the disruptive behavior disorder symptoms: implications from parent ratings for a dimensional approach to symptom validity.

A dimensional approach was used to evaluate the internal validity of the DSM-III-R ADHD-inattention, ADHD-hyperactivity/impulsivity, oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms (i.e., whether a symptom has a stronger correlation with its own dimension that the other three). Parents rated 4,019 children between the ages of 2 and 19 on these symptoms. The results showed that 5 of the 6 inattention symptoms, 3 of the 4 hyperactivity symptoms, 1 of the 4 impulsivity symptoms, 6 of the 9 oppositional defiant disorder symptoms, and 8 of the 11 CD symptoms had significant internal validity. Confirmatory factor analysis (CFA) found support for inattention, hyperactivity/impulsivity, oppositional defiant, and conduct disorder dimensions. Multiple-group CFA also found support for factor pattern and loading invariance across gender. The implications of these results as well as the merits of the dimensional approach to symptom validity are discussed in the context of the DSM-IV changes in ADHD, ODD, and CD.

Adolescent↗
PubMed1997

Murine psoriasis-like disorder induced by naive CD4+ T cells.

Psoriasis is a complex disorder involving alterations of many cell types. Although evidence suggests a T-cell pathogenesis for psoriasis, a primary role of T cells has not been directly demonstrated. Here, we show that reconstitution of scid/scid mice with minor histocompatibility mismatched naive CD4+ T lymphocytes resulted in skin alterations that strikingly resembled human psoriasis clinically, histopathologically and in cytokine expression. This skin disorder was diminished when memory T cells were coinjected. Thus, a subset of dysregulated CD4+ T cells can cause tissue alterations seen in psoriasis without the presence of CD8+ cells or a primary epithelial abnormality.

Animals↗
PubMed1996

p126 (CDw101), a costimulatory molecule preferentially expressed on mucosal T lymphocytes.

Intestinal mucosal lymphocytes are defined by their anatomic location within the epithelium (intraepithelial lymphocytes), the interstitium between the epithelial basement membrane and the underlying muscularis mucosa (lamina propria lymphocytes), or in organized lymphoid tissues (Peyer's patches). Although intestinal intraepithelial lymphocytes have a distinct localization, their function has not been determined. To define cell surface proteins that are involved in intestinal intraepithelial lymphocyte localization or function, cultured human mucosal lymphocytes were used as immunogens to develop mAbs that react predominantly with this cell population in an immunohistochemical screening assay. Three mAbs were selected that subsequently were found by biochemical analysis to identify a 200-kDa homodimeric polypeptide on 88 to 98% of CD3+ mucosal lymphocytes but only 18 +/- 13% of PBLs. Expression on granulocytes and monocytes was also observed. This polypeptide has been termed p126 based on its SDS-PAGE-determined M(r) under reducing conditions. Cleveland digest maps demonstrated similarity between the p126 and CDw101 polypeptides. Determined amino acid sequence analysis of the purified p126 polypeptide revealed that it is the protein product of the recently identified V7 gene, which has structural similarities to members of the Ig gene superfamily. Two of the anti-p126 mAbs were costimulatory with suboptimal concentrations of anti-CD3 mAb inducing proliferation of cultured intestinal intraepithelial lymphocytes. Thus, we conclude that p126 is CDw101 encoded by a gene that predicts a seven-Ig domain chain-like structure. It has restricted expression predominantly on mucosal T lymphocytes and appears to have a costimulatory function of special relevance for CD28- T cells and for mucosal lymphocytes.

Animals↗
PubMed1994

Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin.

In contrast to sessile cell types, lymphocytes migrate through the vasculature to become diffusely distributed in tissues or organized in lymphoid structures. A complex array of adhesion molecules including selectins, integrins and their counter-receptors mediate lymphocyte homing and migration into tissues and may be constitutively expressed or induced. However, the molecules that mediate the tissue-specific retention of lymphocytes within the parenchyma have not been identified. Along the epithelium at the basolateral surface of enterocytes, intestinal intraepithelial lymphocytes are found. These T cells of the mucosal immune system serve as a model for the tissue-specific compartmentalization of lymphocytes. We investigated whether the localization of these intestinal intraepithelial lymphocytes could be mediated by specific interactions between adhesion molecules expressed selectively on this subpopulation of T cells and tissue-restricted adhesion molecules on epithelial cells. Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by E-cadherin and the alpha E beta 7 integrin.

Animals↗
PubMed1994

TCR usage and functional capabilities of human gamma delta T cells at birth.

Little is known about the gamma delta T cells in human neonatal umbilical cord blood. To compare neonatal cord blood and adult blood gamma delta T cells, we studied the V gamma and V delta gene segment usage in these populations by flow cytometry, and we derived cord blood gamma delta T cell clones to determine their functional capabilities. Unlike adult blood gamma delta T cells that predominantly express V gamma 2V delta 2 TCRs, neonatal cord blood gamma delta T cells expressed diverse V gamma and V delta gene segments paired in a variety of combinations rarely observed in adults. gamma delta T cell clones derived from neonatal cord blood similarly expressed a diverse array of TCRs. These cord blood-derived gamma delta T cell clones had weak cytolytic activity when assayed for K562 tumor cell killing, lectin-mediated cytolysis, and redirected cytolysis. They also expressed lower levels of the CD2, LFA-1, and CD45RO cell surface receptors as compared with strongly cytolytic adult gamma delta T cell clones. These properties of the cord blood-derived gamma delta T cell clones, weak cytotoxic activity and low adhesion molecule expression, were similar to the properties of the CD4+ subset of adult gamma delta T cells. Thus, neonatal gamma delta T cells are functionally different from the majority of adult gamma delta T cells and display a distinct TCR repertoire and accessory molecule profile.

Adult↗
PubMed1994

Molecular cloning of the human mucosal lymphocyte integrin alpha E subunit. Unusual structure and restricted RNA distribution.

The human mucosal lymphocyte-1 (HML-1) antigen is expressed on a subclass of T-lymphocytes known as intra-epithelial lymphocytes which are located between mucosal epithelial cells. The HML-1 complex is known to mediate adhesion of intra-epithelial T-lymphocytes to epithelial cell monolayers in vitro. We and others have shown that the HML-1 antigen is an integrin composed of the beta 7 subunit in association with a novel alpha subunit, alpha E. Here we report the cloning of the alpha E cDNA and its primary amino acid sequence. alpha E contained an inserted or I domain and was more homologous to the other I domain containing integrins than to the cleaved group of integrin alpha subunits. However, alpha E contained a unique extra domain of 55 amino acids located just NH2-terminal to the I domain without counterpart in other integrins. This extra domain contained a stretch of 18 consecutive charged residues and included a proteolytic cleavage site. Thus alpha E is the only I domain containing integrin alpha subunit that is also cleaved, and the cleavage site is distinct from that of members of the cleaved group of integrin alpha subunits. These structural features mark alpha E as an unusual member of the integrin family. High levels of alpha E and beta 7 mRNA were restricted to mucosal lymphocytes supporting the hypothesis that alpha E beta 7 plays a role in the localization or site-specific functions of intra-epithelial T-lymphocytes.

Amino Acid Sequence↗
PubMed1994

Distinct structural and functional epitopes of the alpha E beta 7 integrin.

Intestinal intraepithelial lymphocytes (iIEL) are predominantly CD3+, CD8+ T lymphocytes located above or adjacent to the mucosal basement membrane. Although they are positioned to interact with intercellular luminal antigen or with enterocytes, the function of iIEL remains unknown. Most (> 85%) of the iIEL express the alpha E beta 7 integrin which appears to be involved in the adhesion of lymphocytes to epithelial cells. We report the characterization of three monoclonal antibodies (mAb) termed alpha E7-1, alpha E7-2, and alpha E7-3, that react with the alpha E beta 7 integrin recognized by the previously described mAb HML-1 as demonstrated by identical sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility and charge. Flow cytometric analysis of antibody cross-blocking indicated that these mAb recognize distinct epitopes of alpha E beta 7. While all of the mAb were capable of blocking the adhesion of cultured iIEL to a breast epithelial cell line, only HML-1 and alpha E7-1 (which recognize an identical or closely related epitope) were co-stimulatory with suboptimal concentrations of anti-CD3 mAb in inducing proliferation of cultured iIEL. Thus, these mAb appear to recognize functionally distinct epitopes of alpha E beta 7 and will be useful to study relationships between the structure and function of this integrin.

Animals↗
PubMed1994

Evidence for a structural difference in the CD7 polypeptide on human thymocytes and intraepithelial lymphocytes defined by a new monoclonal antibody, 3D9.

Intestinal intraepithelial lymphocytes (IEL) represent a distinct subpopulation of lymphocytes located on or above the basement membrane and adjacent to the basolateral membrane of enterocytes. Thus IEL are strategically positioned to mediate a response to the uptake of foreign antigens or to the alteration of enterocytes by injury or infection. Because of their unique location, we hypothesized that IEL might selectively express specialized cell surface proteins important in their site-specific localization or function. To identify such proteins, we immunized mice with purified human IEL and identified one monoclonal antibody, 3D9, which was found to react with a majority of IEL but with very few lamina propria lymphocytes (LPL) and weakly with most peripheral blood lymphocytes (PBL). Evaluation of this antibody with two-dimensional gels demonstrated that it reacts with CD7, previously known as an early thymocyte differentiation antigen. Interestingly, unlike all other anti-CD7 monoclonal antibodies, 3D9 identified only occasional thymocytes by immunohistochemistry suggesting that CD7 is structurally different on IEL and thymocytes. However, the CD7 polypeptide immunoprecipitated from IEL and thymocytes appeared identical in SDS-PAGE mobility and in charge by two-dimensional gels, despite being recognized differently by monoclonal antibodies. These studies emphasize the expression of CD7 by IEL T cells and reveal the existence of an undefined structural difference between CD7 molecules on IEL compared to thymocytes.

Animals↗
PubMed1994

Murine M290 integrin expression modulated by mast cell activation.

Intraepithelial T lymphocytes possess a (TGF beta)-inducible integrin complex that consists of the beta 7 integrin chain in association with a novel alpha chain, murine alpha M290. Using antibodies directed against the murine alpha M290 chain, IL-3-dependent murine bone marrow-derived mast cells demonstrated positive staining after induction with TGF beta. Sequence information from the human intraepithelial T lymphocyte-alpha E gene sequence was used to clone the murine homolog from a TGF beta-induced T cell library. The murine alpha E homolog gene encodes a protein recognized by antibodies to alpha M290. Expression of this gene by bone marrow-derived mast cells was found to be induced by TGF beta or IgE-mediated cross-linking of Fc epsilon R1. Furthermore, exposure of murine TK-1 cells to supernatants from activated mast cells induces the expression of the alpha M290 gene, indicating that a mast cell mediator(s) can act in a paracrine manner to induce expression of this integrin complex by other cells.

Amino Acid Sequence↗
PubMed1993

Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cells.

Intestinal intraepithelial lymphocytes (iIEL) are a distinct subpopulation of T lymphocytes diffusely distributed in the epithelium. Because > 95% of these iIEL express the integrin alpha E beta 7, we reasoned that this integrin might mediate the localization of iIEL to the epithelium. We report that cultured iIEL bound to mucosal epithelial cells derived from either breast or intestine. This binding was dependent on the presence of divalent cations, and was blocked by mAb specific for two integrins, alpha E beta 7 and alpha L beta 2. After TGF-beta 1 treatment, cultured iIEL cell lines expressed alpha E beta 7 at levels similar to those found on iIEL in vivo. Under these conditions this integrin appeared to predominate in mediating the adhesion of iIEL to epithelial cells. Although alpha L beta 2 blocked the adhesion of iIEL to both endothelial and epithelial cells, alpha E beta 7 blocked binding only to epithelial cells suggesting that the ligand for alpha E beta 7 is not expressed on IL-1 beta-treated cultured endothelial cells. iIEL did not readily bind to the apical surface of confluent polarized epithelial cell monolayers. However, iIEL did bind to these cells when tight junctions were disrupted, a treatment that allows redistribution of proteins compartmentalized to the basolateral surface. This binding was also blocked by mAb to alpha E beta 7. In addition, in vitro coculture of iIEL with polarized epithelial cells resulted in basolateral localization of the iIEL. Thus, it is likely that expression of the alpha E beta 7 ligand is restricted to the basolateral membrane of polarized epithelial cells. Because alpha E beta 7 appears to be a predominant integrin on freshly isolated iIEL, we hypothesized that alpha E beta 7-mediated adhesion may be particularly important in cell-to-cell interactions between T cells and epithelial cells in vivo.

Adult↗
PubMed1993

Alpha 4/180, a novel form of the integrin alpha 4 subunit.

The integrin alpha 4 beta 1 (VLA-4) is a versatile cell-cell and cell-extracellular matrix adhesion receptor. The alpha 4 subunit can be expressed on the cell surface in two forms: an intact form (alpha 4/150) and a cleaved form (alpha 4/80,70). Here we have characterized a third form of alpha 4, called alpha 4/180. Although alpha 4/180 (M(r) 180, nonreduced) is different in size than alpha 4/150 (M(r) 150, nonreduced), these two forms are clearly related, as they (i) shared the same amino-terminal sequence, (ii) were both recognized in Western blots by an anti-alpha 4 COOH-terminal antiserum, (iii) migrated with the same apparent size and charge when reduced, and (iv) were both immunoprecipitated using anti-VLA-4 reagents. In pulse-chase experiments, precursors to both forms appeared simultaneously and matured at the same rate, indicating that one is most likely not the biosynthetic precursor of the other. Although reduction of alpha 4/180 to yield alpha 4/150 suggested the release of a cysteine-linked 30-kDa fragment, seven different biochemical techniques failed to identify such a fragment. Also, alpha 4/180 was converted to alpha 4/150 by incubation at pH 11, by treatment with EDTA at 56 degrees C, or by heating in the presence of elevated SDS levels. Together our findings suggest that alpha 4/180 and alpha 4/150 represent different conformations of the same alpha 4 polypeptide, with the former having anomalous slower migration in SDS-polyacrylamide gel electrophoresis. This unusual biochemical feature of alpha 4 is not shared by other beta 1-associated integrin alpha subunits and suggests that VLA-4 has unique structural properties.

Alternative Splicing↗
PubMed1992

A family of beta 7 integrins on human mucosal lymphocytes.

The heterodimeric protein complex recognized by the human mucosal lymphocyte 1 (HML-1) monoclonal antibody is expressed on 95% of intraepithelial lymphocytes but on only 1-2% of peripheral blood lymphocytes [Cerf-Bensusson, N., Jarry, A., Brousse, N., Lisowska-Grospierre, B., Guy-Grand, D. & Griscelli, C. (1987) Eur. J. Immunol. 17, 1279-1285]. We purified the smaller HML-1 subunit (105 kDa under nonreducing conditions) from hairy-cell leukemia cells and determined the N-terminal amino acid sequence of this chain. The 17 residues determined were identical to the deduced amino acid sequence encoded by an integrin beta 7 cDNA clone [Yuan, Q., Jiang, W.-M., Krissansen, G.W. & Watson, J.D. (1990) Int. Immunol. 2, 1097-1108]. Biochemical analysis of the larger HML-1 subunit (175 kDa under nonreducing conditions) suggested that it was a distinct member of the cleaved group of integrin alpha chains, which we designated alpha E. The beta 7 chain also was associated with the integrin alpha 4 subunit, suggesting that the HML-1 antigen (alpha E beta 7) and alpha 4 beta 7 constitute a beta 7 integrin family on mucosal lymphocytes. Interestingly, regulation of the expression of the HML-1 antigen was reciprocal to that of lymphocyte function-associated molecule 1 in the presence of transforming growth factor beta 1. We suggest that these beta 7 integrins may play a specific role in mucosal localization or adhesion and that the expression of the HML-1 antigen might be regulated by transforming growth factor beta 1 produced at or near epithelial tissues.

Amino Acid Sequence↗
PubMed1992

Functional and structural analysis of VLA-4 integrin alpha 4 subunit cleavage.

The cell surface heterodimer VLA-4 (alpha 4 beta 1), a member of the integrin family of adhesion receptors, is involved in both cell-extracellular matrix and cell-cell adhesion. Unlike any other integrin alpha subunit, the intact (150 kDa) alpha 4 subunit of VLA-4 can sometimes be cleaved into two noncovalently associated fragments (80 and 70 kDa). Using biosynthetic and mixing experiments, we found that human alpha 4 cleavage is a regulated, compartmentalized event, occurring soon after maturation of the beta 1-associated alpha 4 subunit. Cleavage of alpha 4, which is increased following T cell activation, has been suggested to correlate with altered VLA-4 functions. To address directly the functional importance of alpha 4 cleavage, we have studied VLA-4-mediated adhesion functions in cells expressing intact alpha 4 in comparison with cells expressing cleaved alpha 4. For this purpose, we first sequenced the N terminus of the endogenously produced 70-kDa alpha 4 fragment and identified the alpha 4 cleavage site between Lys557-Arg558 and Ser559. To abolish cleavage, we converted Arg558 to Leu or Lys557 to Gln by site-directed mutagenesis of the alpha 4 cDNA and then transfected both mutant and wild type alpha 4 cDNAs into VLA-4-negative K562 cells. Whereas transfection with wild type alpha 4 cDNA yielded predominantly cleaved alpha 4 subunit, the Leu558-alpha 4 yielded only intact alpha 4 subunit, and Gln557-alpha 4 yielded mostly intact alpha 4 subunit. Transfectants with the intact or the cleaved alpha 4 were equally capable of engaging in VLA-4-dependent adhesion to vascular cell adhesion molecule-1 and to the Hep II fragment of fibronectin (40 kDa) and aggregated equally well in response to anti-alpha 4 antibodies. Thus, cleavage of the alpha 4 subunit in these transfectants did not alter any of the known VLA-4-mediated adhesion functions.

Amino Acid Sequence↗
PubMed1992

Total skin electron beam radiation therapy for mycosis fungoides.

Forty-nine patients with biopsy-proven mycosis fungoides, Stages I-IV were treated using total skin electron beam irradiation (TSEBI). Total dose ranged from 600 cGy to 3,200 cGy. To evaluate the dose response relationship, patients were retrospectively divided into two groups. In Group I, 18 patients received a dose of 2,000 cGy or less, and in Group II, 31 patients received more than 2,000 cGy. The overall response rate was 87.7% with a 75.7% complete response and 12.2% partial response. Complete response was higher among patients with early stage disease: (Stage IA 1/1, Stage IB 23/35 (92%), Stage IIA 3/4 (75%), Stage IIB 4/8 (50%), Stage III 3/6 (50%), Stage IVA 1/1, Stage IVB 0/1, and unstaged group 2/3 (66.6%)). Patients treated with a higher total dose had a higher overall 5-year survival rate (Group I 38%, Group II 68%), longer median duration of complete response (Group I, 27 months; Group II, 35.3 months), slightly better complete response rate (72.2% for Group I, 77.4% for Group II), and lower recurrence rate (Group I, 94%; Group II, 83.9%) compared to patients with lower total dose. Complications from TSEBI were minimal. Total skin electron beam irradiation is effective in controlling early stage mycosis fungoides; however, a prospective study to evaluate optimum total dose is needed.

Adult↗