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Biomedical subjects

G Pawelec

Publications and source records attributed to G Pawelec.

At least 37 records · Page 2Linked to original sources
PubMed2001

Recognition of chronic myelogenous leukaemia cells by autologous T lymphocytes primed in vitro against the patient's dendritic cells.

Defects in immune responses are common in patients with chronic myelogenous leukaemia (CML). However, using dendritic cells (DCs) to promote T-cell immunity in vitro may nonetheless elicit potent specific anti-tumour responses for use in immunotherapy. Here, we show that DCs generated from CML patients had a typical dendritic phenotype and were able to stimulate autologous T cells. Three primed T-cell lines were studied in more detail in one patient. They were stimulated by autologous CML cells, but not by normal non-leukaemic cells from the patient's HLA-identical sibling. This was blocked by HLA-DR-specific, but not HLA-DQ- or HLA-DP-specific antibodies. CML-stimulated cytokine secretion, including interferon-gamma and granulocyte macrophage-colony stimulating factor, suggested a Th1-type phenotype for these sensitized anti-leukaemic T cells. This study therefore shows that cells with a functional dendritic phenotype can be generated from the blood of CML patients and are potent inducers of T-cell responses to tumour cells. This approach allows sensitization of patients' T cells by their own particular tumour without the need to identify the exact leukaemia antigens involved, and may find application in immunotherapy of CML.

Cell Division↗
PubMed2000

Hypothesis: loss of telomerase inducibility and subsequent replicative senescence in cultured human T cells is a result of altered costimulation.

Telomerase activity is upregulated after stimulation of human T cells, but as they progress through their finite culture lifespans, this ability is progressively lost. Upregulation of telomerase requires T cell stimulation through the antigen receptor (TCR) and through costimulatory receptors such as CD28. A hypothesis is put forward here that T cell signalling through the TCR is maintained throughout the lifespan of the clones, and that alterations in costimulatory signals are responsible for the progressive loss of telomerase induction. A minimal model of T cell activation during progression through the lifespan is presented in which the TCR provides an unchanging signal 1, but in which there is a progressive decrease in CD28 signalling (signal 2), as well as a decrease in other costimuli, which are here designated as signal 4 (via CD134) and 5 (via CD154). Moreover, in addition, increases in negative costimulation, here designated signal minus 2 (via CD152) and possibly via ICOS (signal 3) may play a part. The balance of these positive and negative signals at each encounter with antigen will determine T cell fate by regulating activation and telomerase induction.

CD28 Antigens↗
PubMed2000

Defensins are dominant HLA-DR-associated self-peptides from CD34(-) peripheral blood mononuclear cells of different tumor patients (plasmacytoma, chronic myeloid leukemia).

The HLA-DR-associated peptides from peripheral blood mononuclear cells of 2 patients with plasmacytoma and 1 with chronic myeloid leukemia were isolated, identified, and compared. Several were identified as derivatives of the defensin family. Defensins (or human neutrophil peptides [HNP]) are antimicrobial, cationic peptides of 29 to 35 amino acids in length and are the major constituents of the azurophilic granules of human neutrophils. Using peripheral blood cells from leukapheresis, containing about 90% of polymorphonuclear cells, we could identify HNP-1, -2, and -4 and propeptides of up to 49 amino acids in length, eluted from HLA class II molecules. Binding of isolated and synthetic defensin peptides to various HLA-DR alleles using an in vitro binding/competition assay based on size exclusion chromatography revealed that defensin may bind into the peptide-binding groove. In a T-cell competition assay, defensins were able to reduce the proliferation of an HLA-DR-restricted T-cell line after preincubation of stimulating cells (CHO-DRB1*0401 transfectants) with defensin. Therefore, binding of defensins might prevent T-cell recognition of HLA class II molecules expressed on different blood precursor cells (all of which are "nonprofessional" antigen-presenting cells) by blocking the HLA peptide-binding groove or, alternatively, might protect defensin-expressing cells from self-destruction. (Blood. 2000;95:2890-2896)

Amino Acid Sequence↗
PubMed2000

In vitro senescence models for human T lymphocytes.

Immunosenescence is an age-associated dysregulation of immune function which may contribute to the increased susceptibility of the elderly to infectious disease. Although age-associated changes are measurable in the innate immune system, it is the adaptive arm of the immune system which is particularly susceptible to the deleterious effects of ageing, especially the T cell compartment. In this review, the characteristics of longitudinal ageing in cultured monoclonal human T cell populations will be summarized. It will be argued that parallels between this in vitro model and T cell senescence in vivo suggest the use of such models to screen for interventions ameliorating immunosenescence in vivo.

Adult↗
PubMed2000

New methods to approach immunotherapy of cancer--and strategies of tumours to avoid elimination. Conference report, on behalf of EUCAPS. European Cancer Research Consortium.

Owing to the intense effort of numerous investigators, the number of tumour antigens potentially of use for clinical immunotherapy continues to increase. At the same time, further strategies employed by tumour cells to avoid destruction by the immune system are being uncovered. A combined onslaught to target tumour cells and prevent their "escape" will be required for successful immunotherapy. Progress in this area was the subject of a meeting supported by the European Cancer Research Consortium "EUCAPS", which was held in London in February 2000. This conference was the second of a series, the first of which was summarised previously in this journal [Pawelec G et al. (1999) Cancer Immunol Immunother 48: 214].

Animals↗
PubMed2000

Longevity in vitro of human CD4+ T helper cell clones derived from young donors and elderly donors, or from progenitor cells: age-associated differences in cell surface molecule expression and cytokine secretion.

The effectiveness of the adaptive immune system relies upon extensive proliferation of an initially small number of antigen-specific T cells. At the end of a successful response, the majority die by apoptosis and a small minority joins the memory cell pool. Upon re-challenge with antigen, these memory cells must again undergo clonal expansion in order to mediate an effective response. Thus, T cells are subjected to marked proliferative stress which may result in clonal exhaustion due to replicative senescence. In other systems made up of rapidly proliferating cells (e.g. in the gut) individual clones are identical and are replaced at the end of their lifespan by differentiation from a stem cell reservoir. However, because of the unique clonal distribution of antigen receptors on T cells, mere replacement with other T cells is not sufficient to maintain the integrity of the system. Moreover, the very source of new T cells decreases with age (due to thymic involution). Therefore, the adaptive immune system may be uniquely susceptible to the deleterious effects of replicative senescence. Particularly in humans, in vivo studies of the behaviour of individual T-cell clones in the body is difficult. However, T-cell longevity, measured as proliferative capacity in terms of population doublings, can be usefully modelled at the clonal level in vitro. This paper discusses the surprisingly little that is known about the average longevity, variation between clones, and the maximal longevity of human T cells under clonal culture conditions in vitro. From our own studies, we show that average lifespan of human T cells is as little as 17 PD; however, established clones reach 35 PD on average, with maximum longevity generally in the region of 60-80 PD, regardless of the source of the cloned cells. Expression of surface molecules in general did not differ strikingly between young and old donors, but the frequency of clones secreting IL-10, and the amount secreted per clone was higher in the elderly than in the young. Conversely, the frequency of clones secreting IL-6 and the amount secreted per clone was higher in the young.

Adult↗
PubMed2000

Escape mechanisms in tumor immunity: a year 2000 update.

The current consensus of opinion has it that most or possibly all tumors, spontaneous as well as induced, are immunogenic, expressing antigens in a form recognizable by the host immune system. Accordingly, in order to progress, tumors have to evolve strategies for evading immune responses. The purpose of this review is to consider the current status of knowledge concerning these different tumor escape strategies. It represents an update of an article originally published in this journal in 1997 (Pawelec, Zeuthen, and Kiessling, 1997). Therefore, it focuses mostly on publications that have appeared since then, illustrating the impressive accumulation of new data since that time and the importance currently attributed to studies of tumor escape from the immune response.

Animals↗
PubMed1999

T cells and aging (update february 1999).

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↗
PubMed1999

Prerequisites for the immunotherapy of cancer.

Tumours express proteins not commonly found in normal cells, or over-express certain proteins. These may in some cases serve as target antigens for immunological attack. It is therefore essential to improve our understanding of the nature of these target epitopes and the cells which recognize them, in order to develop immunotherapy as a realistic treatment for cancer. A small group of around 40 investigators recently came together at the Heinrich Fabri Institute of the University of Tübingen to discuss the identification of human tumour antigens and the exploitation of this knowledge for effective immunotherapy.

Antigen-Presenting Cells↗
PubMed1999

IFN-alpha regulates IL 10 production by CML cells in vitro.

High levels of spontaneous in vitro IL 10 secretion by a subset of untreated chronic phase CML patients' cells are shown to be decreased in the presence of IFN-alpha. However, the lower level of spontaneous IL 10 secretion by healthy control cells are was not depressed by IFN-alpha. In contrast to its effects on IL 10 production, IFN-alpha increased the low spontaneous secretion of IL 1alpha by patients' cells, bud did not further increase the higher levels of spontaneous IL 1beta secretion by normal cells. It had no effect on secretion of TNF-alpha by patients or normals. Spontaneous secretion of IL-1alpha (or IFN-gamma) by patients' cells was not observed whether or not IFN-alpha was present. Therefore, one mechanism of action of IFN-alpha in vivo may involve decreasing endogenous IL 10 secretion (thereby reducing suppressive effects on T cell reactivity) and increasing IL 1beta secretion (thereby enhancing antigen presentation).

Humans↗
PubMed1999

Finite lifespans of T cell clones derived from CD34+ human haematopoietic stem cells in vitro.

Several studies have documented finite lifespans of at least the vast majority of cultured human T cell lines and clones. However, there is a great deal of variation among the different preparations, ranging from < 25 PD up to > 100 PD. The cultured T cells in all these studies originated from mature T cells isolated from peripheral blood of adult donors. It was, therefore, impossible to assess the contribution of differences in in vivo age to the subsequent differences between clones in in vitro aging. In an attempt to circumvent this difficulty, we have developed a culture system that supports the differentiation of highly purified human CD34+ cells into CD3+ T cells in vitro. This features the use of a serum-free medium supplemented with the cytokines flt-3 ligand, IL 3, stem cell factor (c-kit ligand) and IL 2, together with IL 7 or oncostatin M (OM). In this way it is possible to perform "longitudinal" studies on T cells derived de novo in vitro. We show here that T cell clones derived under these circumstances also manifest variable finite life expectancies, for which the only uncontrolled (nonstochastic) effects of aging must already have occurred at the stem cell level.

Adult↗