A large national retail pharmacy chain developed a patient-centric program providing enhanced levels of monitoring and care for patients taking MS Specialty Drugs as dispensed in a retail setting. MS biologics covered in the ConnectedCare for Multiple Sclerosis (CCMS) program during this analysis period included Avonex, Betaseron, Copaxone, Extavia, and Rebif. To compare adherence rates for MS biologics between managed and non-managed patients new to retail pharmacy or the CCMS program. The effect of health complications on adherence rates was also assessed. This was a retrospective analysis of MS patients new to therapy (or pharmacy chain) during the initial six months of CCMS. Patients were followed for one year. Adherence was measured using proportion of days covered (PDC). For the primary objective, propensity scores based on patients’ gender, age, presence of chronic comorbidities, and pre-study adherence to chronic medications were used to match the CCMS intervention group to a comparisons group. Sub-group analysis on health complications (chronic medication comorbidity, or assessment screenings for depression and fatigue) used Analysis of Covariance to adjust for the propensity variables when examining PDC in the presence of health complications across managed cohorts. Mean PDC was nearly 10% higher for the managed CCMS patients than for non-managed patients. Patients not managed with at least one chronic comorbidity had about an 11% lower PDC than non-managed patients without a comorbid condition, whereas, managed patients indicated little difference in relation to the presence of a comorbidity. Adherence levels were also reduced for non-managed patients reporting fatigue and depression, yet self-reports of fatigue and depression did not significantly affect adherence levels among managed patients. The provision of medication therapy management for MS patients significantly increases adherence to MS biologic medications. Among non-managed patients, adherence is even further reduced among patients with fatigue and depression.

Previous research has found that scientific concepts can be meaningfully classified as descriptive (i.e., concepts such as predator and organism with directly observable exemplars) or theoretical (i.e., concepts such as atom and gene without directly observable exemplars). Previous research has also found that developing understanding of descriptive and theoretical concepts is linked to students' developmental levels, presumably because the procedural knowledge structures (i.e., reasoning patterns) that define developmental levels are needed for concept construction. The present study extends prior theory and research by postulating the existence of an intermediate class of concepts called hypothetical (i.e., concepts such as subduction and evolution with exemplars that cannot in practice be observed due to limits on the normal observational time frame). The hypothesis that three kinds of scientific concepts exist was tested by constructing and administering a test on concepts introduced in a college biology course. As predicted, descriptive concept questions were significantly easier than hypothetical concept questions, than were theoretical concept questions. Further, because concept construction presumably depends in part on developmental level, students at differing developmental levels (levels 3, 4, and 5, where level 5 is conceptualized as 'post-formal' in which hypotheses involving unseen entities can be tested) were predicted to vary in the extent to which they succeeded on the concepts test. As predicted, a significant relationship (p < 0.001) was found between conceptual knowledge and developmental level. This result replicates previous research, and therefore provides additional support for the hypothesis that procedural knowledge skills associated with levels of intellectual development play an important role in declarative knowledge acquisition and in concept construction. The result also supports the hypothesis that intellectual development continues beyond the 'formal' stage during the college years, at least for some students. (C) 2000 John Wiley & Sons, Inc.

The primary purpose of the present study was to test the hypothesis that two general developmentally based levels of hypothesis-testing skills exist. The first hypothesized level presumably involves skills associated with testing hypotheses about observable causal agents; the second presumably involves skills associated with testing hypotheses involving unobservable entities. To test this hypothesis, a hypothesis-testing skills test was developed and administered to a large sample of college students both at the start and at the end of a biology course in which several hypotheses at each level were generated and tested; The predicted positive relationship between level of hypothesis-testing skill and performance on a transfer problem involving the test of a hypothesis involving unobservable entities was found. The predicted positive relationship between level of hypothesis-testing skill and course performance was also found. Both theoretical and practical implications of the findings are discussed. (C) 2000 John Wiley & Sons,Inc.

The marrow microenvironment is a complex, three-dimensional structure composed of many cell types and abundant extracellular matrix. Much of the data are derived from analysis of the adherent layer of murine and, especially, human long-term marrow cultures. An essential feature of this in vitro counterpart to the marrow microenvironment is the presence of flat angulated cells functionally defined as marrow stromal cells with the following phenotype: type IV collagen(+), laminin(+), vimentin(+), CD10(+), muscle actin(+), Stro-1(+), and negative for CD45, Mac-1, and HLA-DR. Stromal precursors are Stro-1(+) and CD34(+). Regulation of hematopoietic precursors by the microenvironment occurs by elaboration of regulatory molecules such as hematopoietic cytokines, by cell-cell contact via adhesion molecules such as alpha 4 beta 1 integrin, and by interactions with components of the extracellular matrix as in the case of the glycosaminoglycan hyaluronic acid with cell-associated CD44. Although little about the regulation of stromal cell development itself is known, several studies indicate the transplantability of marrow stromal cells under specific conditions. These developments suggest a potential role of stromal cells in cell therapy. Transfected stromal cells may serve as suitable vehicles for gene delivery to correct single gene disorders in which the product of the target gene does not require stringent regulation as, for example, in the correction of Factor VIII and Factor IX deficiency. Further studies are warranted to investigate marrow stromal cell physiology and regulation to better understand hematopoiesis and to explore the possible use of stroma in therapy.

In a previous report, we showed that cloned T cells incubated with soluble, cognate major histocompatibility complex (MHC) II-peptide complex internalized the peptide moiety of the complex. Here, we report antigen-specific deletion of cloned T cells by treatment with soluble, cognate MHC II-(peptide-toxin) complexes. Toxin (doxorubicin or mycophenolic acid) was attached to synthetic AcMBP(1-14)Ala4 peptide, an analog of the natural acetylated NH2-terminal segment, AcMBP(1-14), of rat myelin basic protein (MBP). IAk-restricted, AcMBP(1-14)-Specific AJ1.2 and 4R3.9 cloned murine T cells were killed by IAk-(AcMBP(1-14)Ala4-toxin). No killing resulted from incubating AJ1.2 and 4R3.9 cells with irrelevant MHC II-(peptide-toxin) or treating IEk-restricted, pigeon cytochrome c-specific A.E7 cloned murine T cells with IAk-(AcMBP(1-14)Ala4-toxin). T cell receptor-mediated T cell uptake of the peptide-toxin moiety of relevant complex was blocked by anti-T cell receptor-alpha/beta antibody and by excess toxin-free complex. LD50 determinations revealed that cognate MHC II-(peptide-toxin) killed T cells much more effectively than did peptide-toxin conjugate alone. Finally, T cell uptake of peptide-toxin and intracellular release of toxin occurred after incubation with relevant MHC II-(peptide-toxin) containing radiolabeled toxin. These findings, which provide the first evidence that cloned T cells can be deleted with soluble, cognate MHC II-(peptide-toxin) complexes, may have significant clinical relevance for antigen-specific therapy of autoimmune or other T cell-mediated diseases.

The initial event triggering the activation of Th cells occurs when the TCR interacts with antigenic peptide in the context of the MHC II on APC. Various T cell accessory molecules including CD4, CD28, and LFA-1 participate and facilitate the activation event. Although some evidence for the interaction of MHC II and CD4 is available, the site of MHC class II (alpha-chain, beta-chain, or both chains) for CD4 interaction has not yet been clearly defined. Results from different laboratories had indicated the involvement of alpha 1, beta 1, and beta 2 domains of MHC class II molecules in CD4 interaction. Recently, a conserved site of DR beta 2 domain has been identified that involves CD4 interaction that is analogous to MHC class I binding site for CD8 molecule. In this report, direct binding of affinity-purified HLA-DR2 dimer and its isolated alpha- and beta-chains to CD4 was studied using a CD4-transfected HeLa cell line. Preferential binding of the beta-chain and intact MHC II dimer to the CD4-transfected cells was observed and found to be specifically inhibited by anti-CD4 mAb. In contrast, the isolated alpha-chain of HLA DR2 did not show significant binding to CD4-transfected cells. Complexes of radiolabeled DR2 dimer or beta-chain alone with an immunodominant epitope from myelin basic protein (83-102) did not show any further increase in binding of these molecules. Binding of the beta-chain to CD4+ cells was markedly inhibited by a DR beta 1 peptide (35-46) and was partially inhibited by a DR beta 2 peptide (134-148) of MHC class II molecule. These results suggest the involvement of at least two conserved regions of the beta polypeptide chain of MHC class II in CD4 interaction. Because in our experiments transfected cells lack TCR molecules and the binding of DR2 to the CD4-transfected cells was unaffected by added antigenic peptide, it is possible that the interaction of MHC class II to CD4 is independent of TCR occupancy.

Antigen presentation to helper T cells involves the formation of a trimolecular complex consisting of a class II major histocompatibility complex (MHC) antigen combined with an antigenic peptide on the surface of an antigen-presenting cell and a T cell receptor (TCR) on the T cell. The fate of the MHC class II, peptide, or TCR moieties of the ternary complex following antigen presentation is unknown. Using radiolabeled complexes of affinity-purified murine MHC class II molecules and peptides corresponding to T cell epitopes of myelin basic protein (MBP), this report presents evidence that the binding of preformed relevant MHC class II-peptide complexes to cloned T cells in vitro results in internalization of the peptide moiety. Neither the restricting MHC class II molecule nor the TCR moiety of the trimolecular complex was internalized by T cells. The specificity of peptide internalization was demonstrated using complexes of syngeneic MHC class II with an irrelevant MBP peptide analog and by cloned T cells restricted for a different epitope of the same MBP antigen. Furthermore, the peptide translocation mediated by MHC class II and TCR was demonstrated by antibody-blocking experiments using anti-class and anti-TCR monoclonal antibodies. The peptide internalization by T cells was markedly reduced when binding was performed at 4 degrees C as compared with 37 degrees C. In addition, a significant inhibition of peptide translocation was observed in the presence of a metabolic inhibitor (sodium azide) but not in the presence of cytochalasin B. These results together demonstrate that the in vitro interaction of soluble MHC II-peptide complexes with cloned T cells is an active process associated with uptake of the antigenic peptide.

Presentation of Ag to the T cell requires binding of specific peptide fragments of the Ag to MHC II molecules. The ability of a peptide to bind to MHC class II appears to be pH dependent. Recent reports indicate that the binding of peptide to MHC class II molecules takes place primarily within an endosomal compartment of the cell at around pH 5. In this study, we have explored the in vitro pH dependence of peptide binding to different haplotypes of murine MHC class II molecules. The binding of peptides to MHC II was analyzed and quantitated by silica gel TLC, using radiolabeled peptides. The MBP peptide fragments, MBP(1-14)A4 and MBP(88-101)Y88, bound maximally at pH 8 to IA(k) and IA(s), respectively. The binding of PLP peptide fragment, PLP(138-151)Y138, to IA(s) was maximal at around neutral pH. The maximum binding of an OVA peptide fragment, OVA(323-340)Y340, to IA(d), was found to occur at pH 6. Results presented in this report thus suggest that the in vitro maximum binding of peptide is pH dependent and does not always occur at pH 5. The optimum pH range for maximum binding may depend on the nature and net charge of the peptide and its interaction with MHC class II molecules.

Haemopoiesis occurs in close physical contact with elements of the bone marrow stroma. This review examines some adhesion molecules which are expressed in haemopoietic environments. These molecules may act to main- tain cell contact between haemopoietic progenitors and the cellular and extracellular matrix elements of the marrow stroma. A review is undertaken of several families of adhesion molecules and their ligands, including inte- grins, CD44, LEC-CAMs, CAMs and variant glycosylation patterns expressed by haemopoietic cells. Both CD44 and integrin receptors have been implicated in mediating important cellular interactions within the haemopoietic system and the significance of these and other molecules in haemopoiesis is discussed.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism of peptide release from major histocompatibility complex class II moleculesStephan N. Witt, Brian R. Clark, and Harden M. McConnellCite this: J. Am. Chem. Soc. 1992, 114, 24, 9680–9682Publication Date (Print):November 1, 1992Publication History Published online1 May 2002Published inissue 1 November 1992https://doi.org/10.1021/ja00050a070RIGHTS & PERMISSIONSArticle Views46Altmetric-Citations13LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (390 KB) Get e-Alerts Get e-Alerts

A specific T cell response to a preformed complex of detergent-solubilized MHC class II molecule and cognate antigenic peptide was observed by monitoring the extracellular acidification. An increase in this rate was observed when the resting 4R3.9 T cell clone specific for the peptide fragment MBP(1-14) of myelin basic protein was exposed to preformed detergent-solubilized IA(k)-MBP(1-14)A4 complexes. MBP peptide alone, IA(k) alone, or complexes of IA(s)-proteolipid protein(139-151) and IA(d)-OVA(323-339), did not cause significant increases in the acidification rates of the MBP(1-14)-restricted 4R3.9 T cell clone. In addition, BW 5147 T lymphoma cells, which lack TCR, did not show any increase in rate when exposed to IA(k)-MBP(1-14)A4 complexes. Similar increases in acidification rate were observed in the presence of IL-2, anti-CD3 and anti-TCR antibodies. The enhanced acidification responses were blocked by genistein, a tyrosine kinase inhibitor.