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G Pawelec

Publications and source records attributed to G Pawelec.

At least 55 records · Page 3Linked to original sources
PubMed1999

T cell immunosenescence in vitro and in vivo.

The term "immunosenescence" refers to an age-associated dysregulation of immune function which contributes to the increased susceptibility of the elderly to infectious disease. Although there are age-associated changes measurable in the innate immune system (Pawelec et al., 1998c), it is the adaptive, particularly T cell, system which is most susceptible to the deleterious effects of aging. In this minireview, characteristics of aging in long-term human T cell cultures will be summarized, and the parallels between the in vitro model and in vivo immunosenescence will be documented. The use of culture models to screen for ways of manipulating immunosenescence in vitro may provide a basis for intervention to ameliorate immunosenescence in vivo.

Aging↗
PubMed1999

Age-related changes in the expression of CD95 (APO1/FAS) on blood lymphocytes.

Aging is associated with alterations of the immune system, thought to be related to an increased susceptibility to infectious diseases, and possibly to cancer and autoimmunity in the elderly. In the present paper we report data obtained on freshly collected blood from 148 healthy subjects of different ages (from cord blood to 102 years old). The subjects were divided into seven age classes (cord blood, 3-11 years, 15-39 years, 41-60 years, 61-74 years, 75-84 years, 85-102 years) and their lymphocyte subsets and the expression of the apoptosis-related molecule CD95 were evaluated. In respect of lymphocyte subsets, the major differences were found in the cord-blood samples compared with the oldest old groups. In the cord-blood group, the absolute number of all the lymphocyte subsets was enhanced, but in the oldest group, an increase of CD16+ lymphocytes was observed, whereas CD19+ lymphocytes, which progressively decrease with age, continue to decrease further in the very old. The data show that the expression of CD95 increases until age 74 years, whereas in the oldest old it tends to decrease again. The trend of CD95 expression seems to be related to the change of expression of CD95 on CD4+ lymphocytes, because the CD8+/CD95+ population rose steadily throughout the entire age range. The evaluation of CD95+/CD45R0+ lymphocytes shows similar results to those observed analyzing CD95 on total lymphocytes. Furthermore, a constant increase of CD95+/CD28+ and a related decline of CD28+ lymphocytes was observed in all age groups. These data suggest that the expression of CD95 on the different subsets of lymphocytes can be considered a good marker for studies of immunosenescence, because it may be predictive of successful aging, and can partially explain the change in lymphocytes subsets in elderly.

Adolescent↗
PubMed1999

Cells and cytokines in immunotherapy and gene therapy of cancer.

An enormous effort using a great variety of approaches has been undertaken in the last decade to translate basic and clinical research into successful cancer therapies. This review summarizes recent results of experiments and trials using cellular and cytokine therapy, as well as gene therapy, to exploit immune responses to tumors.

Animals↗
PubMed1998

Molecular and cellular basis of immunosenescence.

Aged persons and most animals studied show a significant decline in the immune response primarily caused by changes in the T cell compartment. This decline in T cell function is due to a combination of factors: decreased production of new naive T cells by the involuting thymus; extensive antigen-induced activation leading to replicative senescence and clonal exhaustion of certain T cells; and postmitotic aging of resting T cells, a phenomenon also observed in other non-dividing cells such as neurons or muscle cells. The relative importance of these processes in the T cell defective immune response observed in aged humans and animals remains to be established although it is very likely that all of them participate in immunosenescence. The cellular, molecular biological basis and the clinical consequences of the defective immune response in aging were extensively discussed and reviewed at the 5th EUCAMBIS meeting. This paper summarizes the main presentations at the meeting. This special issue contains selected presentations from the congress, in the form of peer-reviewed full papers and the abstracts of two papers previously published in the journal.

Animals↗
PubMed1998

T cells and aging.

Deterioration of the immune system with aging ("immunosenescence") is believed to contribute to morbidity and mortality in man due to the greater incidence of infection, as well as possibly autoimmune phenomena and cancer in the aged. Dysregulation of T cell function is thought to play a critical part in these processes. Factors contributing to T cell immunosenescence may include a) stem cell defects, b) thymus involution, c) defects in antigen presenting cells (APC), d) aging of resting immune cells, e) disrupted activation pathways in immune cells, f) 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.

Aging↗
PubMed1998

Impact of aging on innate immunity.

Immune responses in higher organisms are triggered by the recognition of a limited diversity of microbiological products by cells of the innate or "natural" immune system. As a result, in addition to the direct protective effect of natural immunity, antigen-presenting cells, particularly dendritic cells, are activated to process and present an enormous number of peptide antigens to the T lymphocytes of the adaptive immune system. These, together with the B lymphocytes, then mediate specific immune responses and maintain acquired immunological memory. The aging immune system is less well able to cope with infectious disease than the youthful immune system; this review will briefly consider what is known of the age-associated alterations in innate immunity, and how these may also impact on adaptive immunity.

Aging↗
PubMed1998

Extrathymic T cell differentiation in vitro from human CD34+ stem cells.

Although it is well established that T cells are derived from CD34+ stem cells in vivo, and that T cells can develop in the absence of a functioning thymus, it has not proven possible thus far to generate human T cells in vitro from CD34+ cells in the absence of any thymic influence. We now present a limiting dilution cloning culture system that supports the differentiation of highly purified human CD34+ cells to CD3+ T cells in vitro in the complete absence of any thymic components. The culture system features the use of a serum-free medium supplemented with a cocktail of cytokines including flt-3 ligand, interleukin-3 (IL-3), stem cell factor (SCF), and IL-2. CD4+ T cell clones capable of mitogen-stimulated proliferation and response to IL-2, and expressing a varied TCR-Vbeta repertoire were obtained under these conditions. This culture system therefore supports human T lymphopoiesis in the absence of any thymic influence and may prove useful for the evaluation of extrathymic T cell differentiation in vitro.

Animals↗
PubMed1998

Tumour-specific MHC-class-II-restricted responses after in vitro sensitization to synthetic peptides corresponding to gp100 and Annexin II eluted from melanoma cells.

In a search for potentially tumour-specific MHC-class-II-restricted antigens, the immunogenicity of endogenous peptides that had been eluted from HLA-DR molecules of the human melanoma cell line FM3 (HLA-DRB1*02x, DRB1*0401) was tested in vitro. Two 16-mers representing gp100 positions 44-59, and annexin II positions 208-223 bound well to isolated DRB1*0401 molecules and are discussed here. HLA-DR-matched normal donors' T cells were cultured with peptide-pulsed artificial antigen-presenting cells (CHO cells cotransfected with genes for HLA-DRB1*0401 and CD80 and coexpressing high levels of both human molecules). Specific sensitization was achieved against both peptides, as measured in assays of autocrine proliferation and interleukin-2 secretion. Moreover, responses to native autologous melanoma cells but not to autologous B cells were also observed. In view of the expression of fas by the activated T cells and of fas ligand by the melanoma cells, blockade of potential fas/ fas-ligand interactions was undertaken using monoclonal antibodies (mAb). The antagonistic fas-specific mAb M3, but not the fas agonist M33, caused a markedly enhanced T cell response to FM3 cells. These results demonstrate that synthetic peptide antigens are able to sensitize T cells in vitro for effective MHC-class-II-restricted recognition of melanoma cells.

Animals↗
PubMed1997

Isolation of novel HLA-DR restricted potential tumor-associated antigens from the melanoma cell line FM3.

Endogenous peptides bound to the constitutively expressed MHC class II molecules HLA-DR and HLA-DQ of the melanoma cell line FM3 were examined. By a combination of analytical methods (narrow bore and capillary reversed-phase high-performance liquid chromatography with subsequent spotting on polyvinylidene difluoride membranes, matrix-assisted laser desorption ionization mass spectrometry, and Edman microsequencing), we were able to isolate and identify a panel of HLA-DR4/2 (HLA-DRB1*0401/0201/DRB5*0101)-associated self-peptides from the melanoma cell line FM3. Among ubiquitously HLA-DR-associated peptides such as peptides from the class II-associated invariant chain peptide region of the invariant chain, HLA-class I, the transferrin receptor, and the IFN-gamma receptor, we identified several potential tumor-associated antigens stemming from the MHC class I-restricted tumor antigen gp100, the Ca2(+)-binding protein annexin II, and proteins from the hsp70 family. Chinese hamster ovary cells cotransfected with HLA-DRA, DRB1*0401, and CD80 genes were shown specifically to prime T lymphocytes from HLA-DRB1*0401 donors to the annexin II and gp100 peptides. These results demonstrate that MHC class II molecules expressed by melanoma cells potentially present a variety of novel antigens to the immune system, some of which could be exploited for immunotherapy.

Animals↗
PubMed1997

Interleukin-13 secretion by normal and posttransplant T lymphocytes; in vitro studies of cellular immune responses in the presence of acute leukaemia blast cells.

T lymphocyte secretion of interleukin-13 (IL-13) in response to different activation signals was characterized in vitro. IL-13 release was investigated when virus transformed B lymphocytes or acute myelogenous leukaemia (AML) blasts were used as accessory cells during T cell activation. First, a majority of both CD4+ and CD8+ TCR alpha beta + T lymphocyte clones, derived from normal individuals and bone marrow transplant recipients, secreted IL-13 in response to a standardized mitogenic activation signal (phytohaemagglutinin + IL-2 + B lymphocyte accessory cells). The CD4+ cells showed significantly higher IL-13 levels than the CD8+ subsets. Second, when leukaemic accessory cells (more than 95% AML blasts) were used during T cell activation, IL-13 was released both during alloactivation of normal T lymphocytes and during mitogen activation of posttransplant T cells. Third, when normal T lymphocytes were stimulated with allogeneic AML blasts, addition of IL-13-neutralizing monoclonal antibodies decreased interferon gamma levels. Although addition of IL-13-neutralizing antibodies did not alter granulocyte-colony-stimulating factor secretion by allostimulating AML blasts, altered blast proliferation was detected for certain patients. Thus, most T cell clones can release IL-13, and IL-13 can modulate cytokine responses during T cell recognition of allogeneic AML cells.

Adult↗
PubMed1997

The T cell in the ageing individual.

Aged persons frequently manifest declining parameters of those immune functions which protect the young against disease. Longitudinal studies are beginning to show that number, type and function of T cells may be associated with longevity, morbidity and mortality in free-living elderly humans. Multi-faceted alterations in the ability of T cells from old donors to respond to stimulation are being dissected, and pathways which are compromized in the elderly compared to the young are being defined. Successful immune responses depend upon waves of rapid and extensive clonal expansion to combat primary infection, followed by death of most T cells, survival of memory cells and their later reactivation and further expansion. This implies that the finite replicative potential of T cells might impose a critical limiting factor on the maintenance of immune responses in the face of thymic involution and drastically reduced capacity to generate new naive T cells. This type of 'clonal exhaustion' can readily be studied in vitro using human T cell clones and the findings can be applied to the in vivo situation. Understanding the processes of replicative senescence in such in vitro models may shed light not only on some of the underlying mechanisms of immunosenescence but also in situations of chronic antigenic stimulation in vivo. Moreover, it might begin to indicate how the system could be manipulated on the one hand to prevent or reverse T cell senescence without nullifying the control mechanisms of tumor suppression, and on the other hand, to reconstitute possibly faulty suppression, for example in autoimmune disease.

Adult↗
PubMed1997

Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion?

Extensive in vitro research on fibroblasts has defined numerous genetic and phenotypic changes associated with replicative senescence. Identification of T-cell replicative senescence as a feature of human immunodeficiency virus (HIV) disease and ageing suggests this phenomenon merits more careful consideration by immunologists, especially with regard to chronic infection, memory and adoptive immunotherapy.

Allergy and Immunology↗
PubMed1997

Human T-cell clones in long-term culture as a model of immunosenescence.

We have consistently observed that like other normal somatic tissue cells, human T lymphocytes manifest a finite proliferative capacity in culture in vitro. When measured in population doublings (PD), this averages about 35 PD for T-cell clones (TCC) derived from mature peripheral T cells of young adults and about 20 PD more for TCC derived from T-cell precursors in their bone marrow. We believe that alterations in surface marker phenotypes and corresponding functional changes observed in these human TCC as they progress through their finite lifespans in vitro can provide valuable information on processes of T-cell immunosenescence in vivo. They may also provide a model system for studying ways of modulating the ageing process to delay or prevent immunosenescence in the elderly and the chronically infected or possibly to accelerate immunosenescence in organ transplantation.

Adult↗
PubMed1997

Escape from host-antitumor immunity.

Cancer cells may express proteins recognizable by the individual's immune system as foreign because they are either tumor-specific or not expressed at high levels in normal tissues to which the host is tolerant. There is now much evidence that tumors can be immunogenic, that is, that they frequently express antigens in a form recognizable by the host immune system. This has been shown not only in experimental animals but also for spontaneously occurring human tumors. Tumors therefore may progress by evolving variants that can evade immune responses or by developing other strategies to "escape" the immune response. The purpose of this review is to consider the current status of knowledge concerning these different tumor escape strategies.

Animals↗
PubMed1996

Cytokine modulation of TH1/TH2 phenotype differentiation in directly alloresponsive CD4+ human T cells.

Organ graft rejection is caused by the recognition of allogeneic MHC molecules by recipient T cells by two different pathways. The indirect pathway of alloreactivity requires the presentation of MHC peptides from the graft by autologous APC, as with conventional antigen. The direct pathway, on the other hand, requires the recognition of foreign MHC on foreign cells. The regulatory mechanisms for this component of alloreactivity have not been extensively studied. We show here that the T cell response activated by alloantigens in the direct pathway is similarly constrained and modulated by cytokines, as has been shown for classic antigen presentation. Thus, the inclusion of IL-2 or TGF-beta in MLC performed with purified responder T cells resulted in outgrowth of cells secreting IL-2 and IFN-gamma, whereas addition of IL-4, IL-10, or anti-TGF-beta encouraged outgrowth of cells secreting IL-4 and IL-10. T cells alloactivated via the direct pathway and then cloned in IL-2 alone secreted IL-4 and IL-10 as well as IFN-gamma and IL-2 (Th0 phenotype). Established clones remained susceptible to cytokine modulation, such that IL-4 and IL-10 decreased their secretion of IL-2 and IFN-gamma, whereas TGF-beta suppressed IL-4 and IL-10 secretion. The first alterations of Th0 toward Th1 or Th2 phenotypes could already be observed after only a very brief exposure to cytokines of 48 hr, followed by extended culture with IL-2 alone. These results confirm that human T cells with Th1 and Th2 phenotypes, recognizing alloantigen via the direct pathway, derive from the same IL-2-secreting precursor and can be manipulated by cytokines in an analogous fashion to conventional antigen-reactive cells. These findings may have implications for manipulating the direct pathway of alloantigen recognition in human organ transplantation.

Antibodies↗