Biomedical subjects

Rafael Solana

Publications and source records attributed to Rafael Solana.

At least 19 recordsLinked to original sources

PubMed2006

Human cytomegalovirus infection and T cell immunosenescence: a mini review.

The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an "immune risk profile". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality.

Aged↗

PubMed2006

Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands.

In recent years, studies on the molecular and cellular mechanisms of immune responses against melanoma have contributed to a better understanding of how these tumours can be recognised by cytotoxic cells and the mechanisms they have developed to escape from innate and adaptive immunity. Lysis of melanoma cells by natural killer (NK) cells and cytolytic T cells is the result of a fine balance between signals transmitted by activating and inhibitory receptors. In addition to the T cell receptor, these were initially described as NK cell-associated receptors (NKRs) and were later also found on subsets of T lymphocytes, particularly effector-memory and terminally differentiated CD8 T cells. An increase of NKR(+)CD8(+) T cells has been found in melanoma patients, correlating with the expansion of differentiated effector CD8(+)CD28(null) CD27(null) T cells. NKRs can regulate the lysis of target cells expressing appropriate ligands. Activating receptors recognise ligands on tumours whereas inhibitory receptors are specific for MHC class I antigens and sense missing self. Altered expression of MHC class I antigens is frequently found on melanoma cells, preventing recognition by specific cytolytic T cells but favouring NK cell recognition. Changes in the expression of NKR-ligands in melanoma contribute in explaining the differences in the capacity of cytotoxic immune cells to control melanoma growth and dissemination.

Humans↗

PubMed2006

IL-2 increased RANTES production and CD25 expression in cultured PBMCs only from antiretroviral treated HIV-1+ patients with detectable viral loads.

In order to better understand the possible beneficial effects of intermittent IL-2 treatment as complement of antiretroviral therapy in HIV-1+ patients, we have measured the levels of RANTES in the supernatants and the CD25 expression in cultured PBMCs obtained from HIV-1+ individuals in presence of IL-2. The results showed a significant increases in RANTES production and in the expression of CD25+ in the cultures with IL-2 of PBMC obtained from HIV-1+ patients with a detectable viral load in comparison with both, HIV-1+ patients with no detectable viral loads and with healthy individuals. These results suggest that therapeutic IL-2 administered in addition to highly active anti-retroviral therapy (HAART) may contribute to increase the effect of this therapy by rising both RANTES production and CD25 expression only in HIV-1+ patients with detectable viral loads.

Antigens, CD↗

PubMed2006

Aging and innate immunity.

Adaptive immunity undergoes severe deterioration with age and represents the main problem in the elderly. However, evidence accumulated over the last decade supports the hypothesis that aging also has a profound impact on innate immunity, which in turn markedly impacts the health and longevity of older people.

Aging↗

PubMed2005

CD8 T cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype.

CD8+ T cells can express NK-associated receptors (NKRs) that may regulate their cytolytic function. We have characterized the expression of several NKRs on peripheral blood CD8+ T cells from melanoma patients and compared them to age-matched healthy donors. The analysis performed includes HLA class I specific receptors (KIRs, LILRB1 and CD94/NKG2) and other NK receptors like CD57, CD56 and CD16. Melanoma patients showed a higher variability in the expression of NKRs on circulating CD8+ T cells than age-matched healthy donors. NKR expression on CD8+ T cells from melanoma patients showed a significant increase of KIR2DL2/L3/S2 (mAb gl183), CD244, CD57, CD56 and CD16. We have also found an increase of CD8+ CD28- CD27- T cells in melanoma patients. This subset represents terminally differentiated effector cells expressing CD244 and high levels of perforin. The expression of NKRs was also mainly restricted to this T cell subset. Altogether, circulating CD8+ T cells from melanoma patients display a distinct phenotype characterized by downregulation of costimulatory molecules and higher expression of NKRs. We suggest that the increased expression of NKRs on T cells may contribute to the final outcome of the immune response against melanoma both stimulating or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptor function and enhancing activating receptors may represent new strategies with therapeutic potential against melanoma.

Adult↗

PubMed2005

Human immunosenescence: is it infectious?

Morbidity and mortality due to infectious disease is greater in the elderly than in the young, at least partly because of age-associated decreased immune competence, which renders individuals more susceptible to pathogens. This susceptibility is particularly evident for novel infectious agents such as in severe acute respiratory syndrome but is also all too apparent for common pathogens such as influenza. Many years ago, it was noted that the elderly possessed oligoclonal expansions of T cells, especially of CD8(+) cells. At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunity that were being reported as biomarkers associated with aging. It was discovered that CMV was the prime driving force behind most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells. Independently, longitudinal studies of a free-living population of the very old in Sweden over the past decade have led to the emerging concept of an 'immune risk phenotype' (IRP), predicting mortality, which was itself found to be associated with CMV seropositivity. These findings support our hypothesis that the manner in which CMV and the host immune system interact is critical in determining the IRP and hence is predictive of mortality. In this sense, then, we suggest that immunosenescence is contagious.

Aging↗

PubMed2004

The B-ring substituent at C-7 of colchicine and the alpha-C-terminus of tubulin communicate through the "tail-body" interaction.

The carboxy terminals of alphabeta-tubulins are flexible regions rich in acidic amino acid residues that play an inhibitory role in the polymerization of tubulin to microtubules. We have shown that the binding of colchicine and its B-ring analogs (with C-7 substituents) to tubulin are pH sensitive and have high activation energies. Under identical conditions, the binding of analogs without C-7 substituents is pH independent and has lower activation energy. Beta-C-terminus-truncated tubulin (alphabeta(s)) shows similar pH sensitivity and activation energy to native tubulin (alphabeta). Removal of the C-termini of both subunits of tubulin (alpha(s)beta(s)) or the binding of a basic peptide P2 to the negatively charged alpha-C-terminus of tubulin causes a colchicine-tubulin interaction independent of pH with a low activation energy. Tubulin dimer structure shows that the C-terminal alpha-tail is too far from the colchicine binding site to interact directly with the bound colchicine. Therefore, it is likely that the interaction of the alpha-C-terminus with the main body of tubulin indirectly affects the colchicine-tubulin interaction via conformational changes in the main body. We therefore conclude that in the presence of tail-body interaction, a B-ring substituent makes contact with the alpha-tubulin and induces significant conformational changes in alpha-tubulin.

Animals↗

PubMed2004

Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword?

The coexistence of tumor progression with a tumor-specific immune response constitutes a major paradox of tumor immunity. During the last decade, the presence of cytotoxic T lymphocytes (CTLs) recognising melanoma-associated antigens has been unequivocally demonstrated in numerous different in vivo and in vitro models. However, most often these melanoma-specific T lymphocytes do not control tumor growth. Several mechanisms that involve changes in melanoma phenotype and/or in T-cell differentiation and function could explain the inability of the immune response to control melanoma. In the last few years it has been demonstrated that cellular cytotoxicity is the result of a balance between activating signals triggered by the TCR and costimulatory molecules and inhibitory signals triggered by inhibitory receptors expressed by the CTL. Because the final outcome of the immune response against melanoma depends on the balance between activating and inhibitory signals, the expression de novo on melanoma cells of ligands for inhibitory NKRs and the down-regulation of costimulatory molecules may favor the escape of tumor cells from immunosurveillance. In this paper we review how altered expression of molecules required for T-cell costimulation could result in impaired lysis of melanoma. The modulation of antimelanoma T-cell responses by a group of receptors originally described on NK cells (NK-associated receptors) but which are now known also to be expressed on a subset of cytolytic effector cells is reviewed. We hypothesize that the expression of ligands for NKRs on melanoma cells may contribute to T-cell-mediated immune responses against melanoma either enhancing or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptors or increasing activating receptors could result in new strategies to improve T-cell-mediated rejection of melanoma.

Antigens, CD↗

PubMed2003

HAART induces the expression of HLA-G on peripheral monocytes in HIV-1 infected individuals.

The aim of this work is to analyze if the highly active antiretroviral therapy (HAART) has any effect in the number of peripheral monocytes expressing the tolerogenic molecule human leukocyte antigen G (HLA-G) in HIV-1 infected individuals. In this sense, expression of HLA-G was measured by flow cytometry on peripheral monocytes from HIV-1 antiretroviral-receiving and antiretroviral naïve patients and in HIV-1 patients at different times after the antiretroviral treatments were removed. It was found an increment of monocytes expressing HLA-G in HIV-1 infected individuals receiving HAART, whereas monocytes from untreated HIV-1 patients did not change. When the HLA-G was measured on monocytes after antiretroviral treatment was removed, the number of peripheral monocytes expressing HLA-G was progressively decreasing. These data suggest that antiretroviral therapy is able to induce the expression of the tolerogenic molecule HLA-G on peripheral monocytes from HIV-1 seropositive individuals.

Antiretroviral Therapy, Highly Active↗

PubMed2003

Biogerontology research in Spain.

The article describes the features of biogerontology research in Spain and outlines the research in the biology of ageing, covering a wide spectrum of areas and topics. Research in biogerontology has expanded notably in quality and quantity in the last decades with the development of internationally recognized research groups actively working in the analysis of the complex process of ageing. In the last few years research in ageing has become a priority area in the National Program of Research which has substantially increased funds specifically allocated to biogerontology and biological research on senescence. Despite these improvements, special efforts have to be made not only to consolidate the existing groups but also to facilitate the initiation and development of new research groups in Universities, Hospitals and research institutions with capacity to incorporate trained researchers in this area. It would promote the continuous incorporation of technical and scientific advances in other disciplines to the understanding the biology of ageing and the molecular basis of cellular senescence, that will benefit actual and future ageing population.

Aged↗

PubMed2002

T cells and aging, January 2002 update.

Age-related changes in the immune system may contribute to morbidity and mortality due to decreased resistance to infection and, possibly, certain cancers in the aged. Many studies mostly performed in mice, rats and man but also including monkeys and dogs have established that age-associated immune decline is characterized by decreases in both humoral and cellular responses. The former may be largely a result of the latter, because observed changes both in the B cell germline-encoded repertoire and the age-associated decrease in somatic hypermutation of the B cell antigen receptors are now known to be critically affected by helper T cell aging. As antigen presenting cell (APC) function appears to be well-maintained in the elderly, this review will focus on the T cell. Factors contributing to T cell immunosenescence may include a) altered production of T cell progenitors (stem cell defects, stromal cell defects), b) decreased levels of newly-generated mature T cells (thymic involution), c) aging of resting immune cells, d) disrupted activation pathways in immune cells (stimulation via the T cell receptor for antigen, costimulation, apoptosis control), e) replicative senescence of clonally expanding cells. This review aims to consider the current state of knowledge on the scientific basis for and potential clinical relevance of those factors in immunosenescence in humans. Experiments in other species will be touched upon with the proviso that there are clearly differences between them, especially between humans and rodents, but exactly what those differences are is not completely clear. Given its potential importance and the increasing proportion of elderly people the world over, coupled with the realisation that whereas mortality is decreasing, morbidity may not be decreasing in parallel (1), a better understanding of the causes and impact of immunosenescence may offer the possibility of identifying where prevention or delay of onset, as well as therapeutic intervention, might be beneficial. Amelioration of the effects of dysregulated immune responses in the elderly by replacement therapy, supplementation therapy or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age.

Aging↗

PubMed2002

NK-associated receptors on CD8 T cells from treatment-naive HIV-infected individuals: defective expression of CD56.

OBJECTIVES: This study addresses the detailed expression of natural killer (NK)- associated receptors on CD8 T lymphocytes in treatment-naive HIV-infected individuals. DESIGN: Experimental study analysing the expression of NK-associated receptors on peripheral blood T lymphocytes from HIV-infected individuals compared with healthy controls. METHODS: Flow cytometry was used to analyse the expression of CD56, CD16, CD94, NKG2A, NKB1, CD161, CD244, and perforin, according to the CD28 phenotype, on CD8(bright) T cells obtained from treatment-naive HIV-infected individuals and from healthy controls. RESULTS: The results showed that CD8(bright) T cells from treatment-naive HIV-infected individuals had a decreased expression of CD56 and that CD8(bright)CD56 cell numbers correlated with CD4 cell counts. NK-associated markers were preferentially expressed on CD8(bright)CD28 negative T cells, both in healthy controls and HIV-infected individuals. An increased expression of CD94, CD244, and perforin, which was the consequence of the expansion of the CD8(bright)CD28 negative T-cell subset, was also observed in HIV infection. CONCLUSIONS: As the CD8(bright)CD56 T cells are the mature cytolytic effector cells, the defective expression of CD56 on CD8(bright) T cells shown in HIV-infected individuals could be involved in the decreased peripheral blood T-cell cytotoxicity found in HIV infection.

Adult↗

PubMed2002

Inhibition of CD28-mediated natural cytotoxicity by KIR2DL2 does not require p56(lck) in the NK cell line YT-Indy.

CD28 functions as a cytotoxicity activation receptor in the NK cell line YT-Indy. To analyze the requirement of p56(lck) kinase in the function of killer inhibitory receptors, we transfected the p56(lck) negative YT-Indy cell line with the cl43 gene encoding for KIR2DL2. Pervanadate treatment revealed KIR2DL2 phosphorylation in YT-Indy-cl43, as well as SHP1/SHP2 recruitment. YT-Indy-cl43 cells were inhibited in their ability to lyse target cells expressing HLA-Cw3, a ligand for KIR2DL2. This inhibition was blocked by anti-KIR2DL2 or anti-HLA class I mAb. CD28 crosslinking on YT-Indy-cl43 enhanced tyrosine phosphorylation of PLC-gamma1. The simultaneous ligation of KIR2DL2 with mAb resulted in a decrease in CD28-induced tyrosine phosphorylation of PLC-gamma1 confirming that dephosphorylation of this protein is involved in the KIR2DL2-induced inhibition of CD28-mediated cytotoxicity. As YT-Indy-cl43 did not express detectable levels of p56(lck), these results indicate that this kinase is not required for transmitting the negative signals generated by KIR2DL2 ligation.

CD28 Antigens↗

PubMed2002

Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells.

Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte Ig-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class Ia) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules. In this review we will discuss the molecular structure, specificity, cellular expression patterns, and function of these HLA class I receptors, as well as the chromosomal location and genetic organization.

Antigens, CD↗

PubMed2002

Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals.

Human immunodeficiency virus-I (HIV-1) infected patients show a gradual loss of natural killer (NK) cells that correlates with disease progression. However, the effect of HIV-1 infection on different NK cell subsets has not been fully characterized. In healthy individuals most NK cells are CD3-CD56+ and two different subpopulations, CD56(dim) and CD56(bright), can be distinguished by the mean fluorescence intensity. Although it was originally suggested that CD56(bright) NK cells represent the precursors of the CD56dim subpopulation, recent cumulative data indicate that CD56(bright) and CD56(dim) NK cells are phenotypically, functionally, and developmentally different NK cell subsets. In this study, the analysis of CD56(bright) and CD56(dim) NK subsets showed that neither the number nor the phenotype of CD56(bright) NK cells were significantly altered in treatment-naive HIV-1-infected individuals, whereas the number of CD56(dim) NK cells was decreased. We also have studied NK cell subsets defined by the expression of CD56 in combination with CD16, CD161, or CD94 molecules. Our results demonstrated a preferential decrease of CD3-CD56+ NK cells coexpressing CD16 and CD161 but lacking CD94 molecules. On the contrary an increased percentage of NK cells that do not express CD56 molecules but express CD16, CD161, or CD94 was also found in HIV-1-infected individuals. As it has been proposed that these CD56-negative NK cells expressing other NK cell receptors represent immature NK cells with low cytolytic capacity, our results support that a defective differentiation from immature CD56 negative NK cells to mature CD56(dim) NK cells occurs in HIV-1 infection.

Adult↗

PubMedDate not supplied

Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

Aged, 80 and over↗

PubMedDate not supplied

Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly.

Invariant natural killer T (iNKT) cells represent a well-established T cell lineage characterised in humans by TCR consisting of an invariant alpha chain encoded by Valpha24-JalphaQ genes, paired preferentially with a Vbeta11 chain. iNKT cells also share some characteristics with NK cells, such as the expression of the NK-associated receptor CD161 in humans. The T cell immune response is the most dramatically affected by ageing, although age-associated alterations in the phenotype and function of other cells of the immune system have been demonstrated. Despite the importance of iNKT cells in the regulation of the immune response, there are a limited number of studies on the effect of ageing on peripheral blood iNKT cells. Thus, in this work we analyse the effect of ageing on peripheral blood Valpha24(+)Vbeta11(+) iNKT cells by studying their frequency, phenotype and proliferative function in elderly individuals fulfilling the SENIEUR criteria of healthy ageing compared with healthy young donors. Our results demonstrated a significant decrease of the percentage of Valpha24(+)Vbeta11(+) iNKT cells in elderly donors. No significant differences were found in the expression of CD27, CD28, CD45RO, CD45RA(bright), CD161, CD94 and NKG2D on iNKT cells from young and elderly individuals. Proliferation of Valpha24(+)Vbeta11(+) iNKT cells in response to alpha-GalCer and IL2 was analysed by calculating the cumulative population doubling (PD) after 14 days of culture. The PD levels were lower in the elderly indicating that Valpha24(+)Vbeta11(+) iNKT cells from healthy elderly subjects had an impaired proliferative capacity. These results indicate that ageing associates with a significant decline in the percentage and proliferative response of peripheral blood iNKT cells. Given the important immunoregulatory role of iNKT cells, these alterations in their number and function could contribute to the deleterious immune response in the elderly.

Adult↗

PubMedDate not supplied

Basic biology and clinical impact of immunosenescence.

Immunosenescence is an age-associated decline of immunity involving multiorgan changes. As the mean age of the population increases, an increase of diverse pathologies associated with immunosenescence has been observed in the developed countries. Age-related changes in the immune system contribute to the increased incidence and severity of infectious diseases and possibly cancer in the elderly. Moreover, in young individuals chronic activation of the immune system (as occurs in autoimmune diseases, cancer, HIV infection and other chronic infections) induces changes in the immune response that parallel those observed in elderly individuals. An interdisciplinary approach to immunosenescence including investigation of the molecular and cellular mechanisms and clinical aspects is being utilised by the EU program "Immunology and Ageing in Europe" (ImAginE, QLK6-CT-1999-02031), the second major international conference of which took place in Córdoba, Spain, 22-26th March, 2001). We briefly summarise some of the highlights of the meeting here, and bring together in this special issue a collection of peer-reviewed papers reflecting the broad approach to immunosenescence currently being applied.

Aging↗