Effects of a new topical combination on sensitive skin.

Using well-tolerated cosmetics or those with soothing effects is recommended to treat sensitive skin. However, we lack clinical studies. Two clinical trials were performed on sensitive skin in France and Thailand. The primary objective was to evaluate the preventive soothing effect. The secondary objectives were to evaluate the immediate soothing effect, product tolerance, and impact on quality of life. Evaluation methods included a stinging test and scoring erythema and stinging intensity. We also assessed tolerance, quality of life using the Dermatology Life Quality Index, and cosmetic qualities. The clinical trials were performed in France and Thailand to test efficacy in two different environments and on different ethnic skin. Interesting effects were observed in patients with sensitive skin in France and Thailand: a preventive soothing effect, a soothing effect on erythema, and an immediate soothing effect. In vivo biometrological, sodium lauryl sulfate, and capsaicin tests confirmed these data. A favorable effect on quality of life was also noted. The product was appreciated by volunteers for its efficacy, tolerance, and cosmetic qualities. A preliminary study on the effects on interleukin 8 was also included in the paper.

Review article: antitumoural immunity in colorectal cancer - current and potential future implications in clinical practice.

BACKGROUND: Most of the current research in gastrointestinal oncology is focused on biology of cancer itself, but there is growing interest in the patient's immune system response and its relation with cancer cells. AIM: To review the impact of the antitumoural immune response on epidemiology, prognosis and treatment of colorectal cancer. METHODS: Search of the literature published in English using the PubMed database. RESULTS: The role of the immune system in the antitumoural immunosurveillance is clearly supported by the increased incidence of colorectal cancer and adenomatous polyps in immunosuppressed patients. Moreover, the degree of infiltration of the tumours by the immune cells has been shown to be a strong prognostic factor of both disease recurrence and survival. The immune system plays an important role in the chemotherapy-induced cell death. New therapeutic strategies targeting the antitumoural immunity are being currently investigated with promising results. CONCLUSION: Better knowledge of antitumoural immune system can have a major impact on patients' management in daily clinical practice. Colorectal cancer screening is an important issue in immunosuppressed patients, and recommendations should be refined for selected high-risk patients. The use of an immune score to guide the therapeutic strategies in the adjuvant setting should be supported. Further and larger clinical trials are necessary to accelerate the development of innovative immune therapies.

Gamma delta T cell receptors.

Gamma delta (gamma delta) T cells are among the least understood components of the immune system. While these cells appear to contribute uniquely to host immune competence, defining their functions in the context of host biology and pathology has been difficult. This is largely because it is unclear what antigens the gamma delta T cell receptor repertoire is directed against. During the past year, there have been noteworthy advances in this area. Their significance in the context of gamma delta T cell biology is discussed.

Asymptomatic deficiency in the peptide transporter associated to antigen processing (TAP).

Human HLA class I deficiency is a rare disease which, in most of the patients described to date, results from a defect in subunit 1 or 2 of the peptide transporter associated with antigen processing (TAP). The clinical features of TAP deficiency include a chronic inflammation of the respiratory tract and/or granulomatous skin lesions. In this report, we describe two adult siblings with an HLA class I deficiency. One individual had only spontaneously-healing skin granulomatous lesions, while the second did not display any of the symptoms associated with HLA class I deficiency and could be considered to be healthy. We show that the patients display a homozygous TAP2 mutation which blocks the maturation of HLA class I molecules. Cell surface expression of these molecules is strongly reduced, but three times higher than on cells from other previously described TAP-deficient individuals. This higher expression results, at least in part, from the presence of HLA-B7 molecules which are probably empty of peptide. The numbers of CD8+ alphabeta T cells are almost normal in these patients. The anti-EBV T-cell response of one patient is mediated by HLA-B7 restricted CD8+ alphabeta T lymphocytes recognizing the BMRF1 nuclear EBV antigen, demonstrating that CD8+ alphabeta T cells can participate in anti-viral responses. This study shows that TAP deficiency can remain totally asymptomatic for several decades, and suggests that in some cases, TAP-independent immune responses provide efficient protection from most of the common intracellular pathogens.

Immunodominant CD8 T cell response to Epstein-Barr virus.

Epstein-Barr virus (EBV) provides one of the most informative systems for analysing cytotoxic T lymphocyte responses in humans. The viral infection and its persistence are the results of an alternation of lytic and latent phases that are controlled by the immune response. Using a transient COS transfection assay that permits semi-quantitative estimation of CD8 T cell responses against a large number of HLA/viral protein combinations, we analyzed responses to EBV within a large number of polyclonal T cell lines. This allowed a rapid identification of major epitopes and the demonstration that EBV-specificT cells were mainly directed against a restricted set of immunodominant epitopes, primarily generated during the early lytic cycle. Knowledge of the antigen specificity of CDB T cell responses against EBV should help generate cytotoxic T cell lines to this herpesvirus, and more generally to study the molecular basis of immunodominance.

The tight interallelic positional coincidence that distinguishes T-cell receptor Jalpha usage does not result from homologous chromosomal pairing during ValphaJalpha rearrangement.

The T-cell receptor (TCR) alpha locus is thought to undergo multiple cycles of secondary rearrangements that maximize the generation of alphabeta T cells. Taking advantage of the nucleotide sequence of the human Valpha and Jalpha segments, we undertook a locus-wide analysis of TCRalpha gene rearrangements in human alphabeta T-cell clones. In most clones, ValphaJalpha rearrangements occurred on both homologous chromosomes and, remarkably, resulted in the use of two neighboring Jalpha segments. No such interallelic coincidence was found for the position of the two rearranged Valpha segments, and there was only a loose correlation between the 5' or 3' chromosomal position of the Valpha and Jalpha segments used in a given rearrangement. These observations question the occurrence of extensive rounds of secondary Valpha-->Jalpha rearrangements and of a coordinated and polarized usage of the Valpha and Jalpha libraries. Fluorescence in situ hybridization analysis of developing T cells in which TCRalpha rearrangements are taking place showed that the interallelic positional coincidence in Jalpha usage cannot be explained by the stable juxtaposition of homologous Jalpha clusters.

Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes.

Contribution of Vgamma9/Vdelta2 T lymphocytes to immune protection against Mycobacterium tuberculosis is still a matter of debate. It was reported earlier that Vgamma9/Vdelta2 T lymphocytes kill macrophages harboring live M. tuberculosis through a granule-dependent mechanism that results in killing of intracellular bacilli. This study found that Vgamma9/Vdelta2 T lymphocytes reduce the viability of both extracellular and intracellular M. tuberculosis. Granulysin and perforin, both detected in Vgamma9/Vdelta2 T lymphocytes, play a major role, which indicates that Vgamma9/Vdelta2 T lymphocytes directly contribute to a protective host response against M. tuberculosis infection.

Structure of a human gammadelta T-cell antigen receptor.

T-cell antigen receptors composed of gamma and delta polypeptide chains (gammadelta TCRs) can directly recognize antigens in the form of intact proteins or non-peptide compounds, unlike alphabeta TCRs, which recognize antigens bound to major histocompatibility complex molecules (MHC). About 5% of peripheral blood T cells bear gammadelta TCRs, most of which recognize non-peptide phosphorylated antigens. Here we describe the 3.1 A resolution structure of a human gammadelta TCR from a T-cell clone that is phosphoantigen-reactive. The orientation of the variable (V) and constant (C) regions of the gammadelta TCR is unique when compared with alphabeta TCRs or antibodies, and results from an unusually small angle between the Vgamma and Cgamma domains. The complementarity-determining regions (CDRs) of the V domains exhibit a chemically reasonable binding site for phosphorylated antigens, providing a possible explanation for the canonical usage of the Vgamma9 and Vdelta2 gene segments by phosphoantigen-reactive receptors. Although the gammadelta TCR V domains are similar in overall structure to those of alphabeta TCRs, gammadelta TCR C domains are markedly different. Structural differences in Cgamma and Cdelta, and in the location of the disulphide bond between them, may enable gammadelta TCRs to form different recognition/signalling complexes than alphabeta TCRs.

Y2K+1 state-of-the-art on non-peptide phosphoantigens, a novel category of immunostimulatory molecules.

Some human T cells are activated in vivo and in vitro by small non-peptide antigens, so-called phosphoantigens. Since their discovery in 1994, several reports have continuously documented novel members of this category of immunostimulatory molecules. This article reviews the current knowledge on their biochemical properties.

Comprehensive analysis of the frequency of recognition of melanoma-associated antigen (MAA) by CD8 melanoma infiltrating lymphocytes (TIL): implications for immunotherapy.

Fifty-nine tumor-infiltrating lymphocyte (TIL) cultures established from melanoma-invaded lymph nodes were screened for recognition of 28 melanoma-associated antigens (MAA) in association with31 HLA molecules. Twenty-three (39%) TIL lines reacted to at least one melanoma antigen. Melanosomal proteins were recognized by 19 TIL populations and the most prominent responses against these proteins were directed against Melan-A/MART-1 (mainly in association with HLA-A*0201) and gp100 (in association with diverse HLA contexts). Ten TIL populations reacted against 10 tumor-specific antigens, in association with 8 different HLA molecules. HLA-A*0201 and B*3501-restricted responses were the most frequent with, respectively, 17 and 7 responses directed against 5 distinct antigens. Unexpectedly, the recognition by TIL of different MAA was frequently restricted by a single HLA in individual tumors, and there was no evidence for the existence of dominant MAA epitopes between tumors,except for Melan-A/MART-1 antigen. This analysis also led to the detection of 21 new HLA-peptide complexes recognized by melanoma TIL. This study, which is to our knowledge the most comprehensive analysis of TIL specificity to tumor antigens, has several implications for the design of immunotherapeutic strategies based on immunization against selected tumor epitopes.

Chemical synthesis and biological activity of bromohydrin pyrophosphate, a potent stimulator of human gamma delta T cells.

Small phosphorylated metabolites from mycobacteria stimulate human gammadelta T lymphocytes. Although such phosphoantigens could prove useful in the composition of vaccines involving gammadelta T cell-mediated immunity, their very low abundance in natural sources limits such applications. Here, we describe the chemical production, purification, and bioactivity of a phosphorylated bromohydrin (BrHPP) analogue that mimics the biological properties of natural phosphoantigens. This compound can be obtained in gram amounts, is easy to detect, and is of high stability in aqueous solutions. Whereas unspecific binding of BrHPP to a wide panel of cell surface receptors is not detected even at micromolar concentrations, nanomolar concentrations specifically trigger effector responses of human gammadelta T lymphocytes. Thus, BrHPP is a novel molecule enabling potent immunostimulation of human gammadelta T lymphocytes.

Paper alert. Immunology.

A selection of interesting papers that were published in the two months before our press date in major journals most likely to report significant results in immunology.

Frequent recognition of BCRF1, a late lytic cycle protein of Epstein-Barr virus, in the HLA-B*2705 context: evidence for a TAP-independent processing.

Using a transient COS transfection assay, allowing a rapid estimation of the dominant CD8(+) T cell responses against a large number of HLA/viral protein combinations within polyclonal cell lines, we searched for HLA-B*2705-restricted CD8 T cell responses to Epstein-Barr virus (EBV) within T cell samples enriched for EBV-reactive cells. Among the 18 EBV proteins tested, only 2, the latent protein EBNA3A and the late lytic protein BCRF1 (viral IL-10), appeared dominant in the B27 context, as they triggered significant TNF and cytolytic responses in some donors. We provide evidence that the B27/BCRF1 epitope (RRLVVTLQC) is located in the signal sequence and that it can be presented in a TAP-independent manner. Using B27/BCRF1 monomeric complexes coated on immunomagnetic beads, we sorted out BCRF1-specific CD8 T cells from 8 of 15 HLA-B27(+) donors. This is, to our knowledge, the first demonstration of a recognition of BCRF1, suggesting that some immune control against EBV exists even during the late stage of the lytic cycle. This result also strengthens the unusual ability of HLA-B*2705 to present peptide in a TAP-independent manner.

Regulation of inhibitory and activating killer-cell Ig-like receptor expression occurs in T cells after termination of TCR rearrangements.

A small fraction of T cells expresses killer-cell Ig-like receptors (KIR), a family of MHC class I-specific receptors that can modulate TCR-dependent activation of effector functions. Although KIR(+) cells are enriched within Ag-experienced T cell subsets, the precise relationships between KIR(+) and KIR(-) T cells and the stage of KIR induction on these lymphocytes remain unclear. In this study, we compared KIR(-) and KIR(+) alphabeta T cell clones, sorted by means of the CD158b (KIR2DL2/KIR2DL3/KIR2DS2) specific mAb GL183. We isolated several pairs of CD158b(+) and CD158b(-) alphabeta T cell clones sharing identical productive and nonproductive TCR transcripts. We showed that expression of functional KIR on T cells is regulated after termination of TCR rearrangements. Transcriptional regulation of KIR genes was documented in multiple T cell clones generated from the same donor, and the presence of KIR transcripts was also detected in KIR(-) T cells. These results document a complex regulation of KIR expression in T cells at both pre and posttranscriptional levels, under the control of yet undefined signals provided in vivo.

egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus.

The recently described staphylococcal enterotoxins (SE) G and I were originally identified in two separate strains of Staphylococcus aureus. We have previously shown that the corresponding genes seg and sei are present in S. aureus in tandem orientation, on a 3.2-kb DNA fragment (Jarraud, J. et al. 1999. J. Clin. Microbiol. 37:2446-2449). Sequence analysis of seg-sei intergenic DNA and flanking regions revealed three enterotoxin-like open reading frames related to seg and sei, designated sek, sel, and sem, and two pseudogenes, psi ent1 and psi ent2. RT-PCR analysis showed that all these genes, including seg and sei, belong to an operon, designated the enterotoxin gene cluster (egc). Recombinant SEG, SEI, SEK, SEL, and SEM showed superantigen activity, each with a specific V beta pattern. Distribution studies of genes encoding superantigens in clinical S. aureus isolates showed that most strains harbored such genes and in particular the enterotoxin gene cluster, whatever the disease they caused. Phylogenetic analysis of enterotoxin genes indicated that they all potentially derived from this cluster, identifying egc as a putative nursery of enterotoxin genes.

Autoreactivity by design: innate B and T lymphocytes.

Innate B and T lymphocytes are a subset of lymphocytes that express a restricted set of semi-invariant, germ-line-encoded, autoreactive antigen receptors. Although they have long been set apart from mainstream immunological thought, they now seem to represent a distinct immune-recognition strategy that targets conserved stress-induced self-structures, rather than variable foreign antigens. Innate lymphocytes regulate a range of infectious, tumour and autoimmune conditions. New studies have shed light on the principles and mechanisms that drive their unique development and function, and show their resemblance to another subset of innate lymphocytes, the natural killer cells.