The Impact of Pre-exposure Prophylaxis on Sexual Well-Being Among Men Who Have Sex with Men

Archives of Sexual Behavior - Pre-exposure prophylaxis (PrEP) is a promising strategy to reduce HIV incidence among men who have sex with men (MSM). How and when PrEP is used could in part be...     

Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution.

The existence of at least three alleles of the HLA-DRB3 gene within the human population is evident. These alleles express DRw52 determinants and react with monoclonal antibody (mAb) 7.3.19.1. The polymorphic epitope recognized by 7.3.19.1 is not only present on human cells but is also expressed on chimpanzee (Pan troglodytes) class II-positive cells. The 7.3.19.1 determinant already existed before speciation of man and chimpanzee, and is at least 5,000,000 yr old. Two-dimensional gel electrophoresis demonstrated that the various HLA- and Patr-DRw52 molecules that are reactive with 7.3.19.1 exhibit isoelectric point differences due to primary amino acid heterogeneity, as was confirmed by sequencing data. Sequence comparison allowed us to map the binding site of mAb 7.3.19.1 to the alpha helix of the major histocompatibility complex (MHC) class II DRB1 domain surrounding the antigen-binding cleft. Despite MHC sequence variation, chimpanzee antigen-presenting cells can present antigen (purified protein derivative) to human T cell lines and vice versa. Only the HLA- and Patr-DRw52 molecules were shown to function as restriction elements for antigen presentation across this species barrier. It is concluded that these particular restriction determinants probably have been conserved in evolution. The HLA- and Patr-DRw52 molecules represent alleles displaying polymorphism that has been selected for in evolution. Such "biomutants" may thus be more useful to study the biological significance of MHC molecules than MHC variants that have been generated by in vitro mutagenesis experiments.     

The immunomodulatory actions of E-type prostaglandins

Prostaglandins (PGs) have been recognised as modulators of immune responses. This has been proved by both in vitro studies and from observations in animals and humans. Administration of prostaglandins for therapeutic purposes, however, has been hampered by their limited bioavailability and their pleiotropic effects, with resultant toxicological profile. Despite this, some success has been demonstrated in the clinic for the control of graft rejection, especially when used as part of a broader immunosuppressant regimen. Full realisation of the therapeutic potential of prostaglandins will depend on a better understanding of their mechanism of action at the cellular level. Recently, it has been appreciated that prostaglandins do not merely inhibit T-cell function, but appear to modulate the profile of lymphocyte sub-populations through regulation of cytokine synthesis and release. Recent efforts have also begun to focus on identifying prostaglandin receptor subtypes important for immune regulation and offer a means, together with targeted delivery, of utilising the immunosuppressant/anti-inflammatory effects of E-type prostaglandins in a safe and effective manner.     

Immunology in medical practice. XIX. Etiology and pathogenesis of auto-immune diseases]

In spite of the collection in the last 50 years of an enormous amount of knowledge about aetiology and pathogenesis of autoimmune diseases, important questions have not yet been answered (adequately), as shown by the very limited therapeutic application of this knowledge. Although autoreactive B and T cells are demonstrable in healthy individuals, this does under normal circumstances not lead to disease, for instance because necessary co-factors are lacking, B lymphocytes for antibody production require help from suitable autoreactive T helper cells, because of the action of T suppressor cells and due to anti-idiotypic antibodies and T cell receptors that may be directed against the antigen receptors of autoreactive B and T cells. Autoimmune diseases are sometimes subdivided into organspecific (e.g. Graves' disease) and systemic autoimmune diseases (e.g. disseminated lupus erythematosus). Roughly speaking there are two hypotheses concerning the aetiology or development of autoimmune diseases. The first hypothesis assumes a specific antigen as the driving factor, the second dysregulation of the immune system. The new insights into the pathogenesis of autoimmune diseases so far led to development of only few new drugs or therapies.     

Limitations of homology searching for identification of T-cell antigens with library derived mimicry epitopes.

Mimicry epitopes that are recognized by T-cells can be identified through screening of synthetic peptide libraries. We have shown that these mimicry epitopes share sequence similarity with the corresponding natural epitopes and that mimicry sequences can be used for the definition of protein derived T-cell epitopes from databases. This can be done by either homology searching or pattern searching. Here we discuss the advantages and disadvantages of homology searching as an alternative for the generally applicable recognition pattern approach. We show that only for part of the library derived mimicry epitopes, the degree of similarity to the natural epitope may be high enough for successful homology searching in small databases.     

Gender differences in sarcoidosis: symptoms, quality of life, and medical consumption

The aim of this study was to examine gender differences in quality of life (QOL) and in constitutional symptoms that coincide with sarcoidosis. The study population included 1026 sarcoidosis patients--all members of the Dutch Sarcoidosis Society--who completed the WHOQOL-100 and a symptom checklist. Women experienced more symptoms than men. With regard to QOL, male and female patients who suffered from symptoms differed in the broader domains of Physical Health and Psychological Health. Specific facets reflected pain, sleep, positive affect, appearance, mobility, and activities of daily living. Future studies should focus on the different experience of the disease between male and female patients more extensively. Studies are needed to evaluate whether the differences in the present study between male and female sarcoidosis patients are caused by a subject selection bias or life style differences; have a genetic, hormonal or biological base; or just are an epiphenomenon.     

ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1

The present study was performed to investigate the ability of the multidrug resistance protein (MRPI) to transport different cationic substrates in comparison with MDR1-P-glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC4/Adr) and a MRP1-transfected cell line (S1(MRP)). As substrates we used 3H-labelled derivatives of the hydrophilic monoquaternary cation N-(4',4'-azo-in-pentyl)-21-deoxy-ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1-substrates. MRP1 did not mediate transport of these substrates per se. In the presence of reduced glutathione (GSH), there was an ATP-dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC4/Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1-inhibitor MK571. ATP- and GSH-dependent transport of daunorubicin and vincristine into GLC4/Adr membrane vesicles was inhibited by the MRP1-specific monoclonal antibody QCRL-3. MRP1-mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations > or = 10 mM. The apparent KM value for GSH was 2.7 mM. Transport of daunorubicin in the presence of 10 mM GSH was inhibited by MK571 with an IC50 of 0.4 microM. In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP- and GSH-dependent manner. APDA is not a substrate for MRP1.