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At least 1,423 records · Page 79Linked to original sources
PubMed1998

Rapid assessment of antigen induced cytokine expression in memory T cells by flow cytometry.

Methods for analysis of T cell responses to specific antigen have traditionally relied on measurements of proliferation or cytokine expression in bulk cultures of PBMC in long term incubations with putative antigen. These techniques suffer from the drawback that they do not enable analysis of single cell responses in the context of unselected cellular backgrounds. It is increasingly important to not only identify cells on the basis of expression of unique surface antigens but also to determine functional and molecular parameters of individual cells in response to a variety of stimuli. We have recently developed methodologies to rapidly assess T-cell subset responses to polyclonal activators and specific antigen in whole blood. These procedures determine the percentages of activated cells and the identification of leucocyte subsets capable of expressing various cytokines and cell surface antigens. Multiparameter analysis of CD69+ /cytokine + expression in T cells in response to specific antigen (e.g. CMV, mumps) demonstrated a range of frequencies from 0.05% to 5.0% within 6 h. Frequencies of responding T cells were consistent but varied depending upon the antigen. Antigen specific T cell responses were host specific and both positively and negatively regulated by antibodies to co-receptors involved in APC-T cell interactions. These technologies will be discussed in terms of application to problems of measuring immune function parameters in disease. The modified technique described in this report is compatible with simple and rapid analysis of clinical samples and provides a means to directly examine the effects of in vivo drug concentrations on T cell immunity. Studies are in progress to examine the sensitivity of this cellular assay to drugs and other therapeutic modalities in clinical samples.

Antibodies, Monoclonal↗
PubMed1992

Memory T cells of a patient with follicular thyroid carcinoma recognize peptides derived from mutated p21 ras (Gln-->Leu61).

Point mutations in ras genes resulting in substitutions of amino acid Gly in positions 12 and 13, and Gln in position 61 of the ras gene product p21, are commonly found in human tumors. Peptides derived from aberrant p21 may elicit a tumor specific T cell response, provided that these peptides can bind to HLA molecules of the tumor and the patient has T cells able to recognize the corresponding peptide-HLA complex. Here we report that CD4+ T cells of memory type (CD45RO+) from a patient with a follicular thyroid carcinoma respond against a synthetic peptide derived from aberrant p21 ras having a Gln-->Leu substitution at position 61. Such responses were not observed when T cells from healthy volunteers or cancer patients where this mutation does not usually occur were stimulated with this peptide. The responding T cells did not cross-react with the corresponding peptide derived from native p21 ras nor did they recognize peptides carrying other substitutions in position 61. T cells clones were generated which recognized this Leu61 peptide when presented by HLA-DQ8 molecules. These T cell clones also recognized the corresponding intact p21 ras protein. By using several different synthetic peptides, a peptide with optimal stimulatory capacity was defined. Performing polymerase chain reaction and oligonucleotide probing we were, however, not able to detect the p21 ras gene encoding the Gln-->Leu substitution in DNA from tumor biopsies from the patient. This may indicate that tumor cells harboring the mutation leading to the Gln-->Leu substitution had been eliminated and that tumor progression was due to cells that had deleted the mutated ras gene. The finding that ras derived peptides and recombinant mutated p21 ras are immunogenic in man may form the basis for the development of cancer immunotherapy based on synthetic oncogene derived peptides.

Adenocarcinoma↗
PubMed1999

An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions.

It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-1(27-35)-specific CTL precursors (CTLp) were >/=1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO(+) memory T cell subset. In the remaining five patients, a low (<1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA(+) naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a "brisk" or "nonbrisk" CD3(+)CD8(+) T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.

Adult↗
PubMed1994

Immune networks modeled by replicator equations.

In order to evaluate the role of idiotypic networks in the operation of the immune system a number of mathematical models have been formulated. Here we examine a class of B-cell models in which cell proliferation is governed by a non-negative, unimodal, symmetric response function f (h), where the field h summarizes the effect of the network on a single clone. We show that by transforming into relative concentrations, the B-cell network equations can be brought into a form that closely resembles the replicator equation. We then show that when the total number of clones in a network is conserved, the dynamics of the network can be represented by the dynamics of a replicator equation. The number of equilibria and their stability are then characterized using methods developed for the study of second-order replicator equations. Analogies with standard Lotka-Volterra equations are also indicated. A particularly interesting result of our analysis is the fact that even though the immune network equations are not second-order, the number and stability of their equilibria can be obtained by a superposition of second-order replicator systems. As a consequence, the problem of finding all of the equilibrium points of the nonlinear network equations can be reduced to solving linear equations.

Animals↗
PubMed2005

Innate-like B cells.

Numerous studies in several species have shown that certain subsets of T and B lymphocytes express antigen receptors which are either semi-invariant, or germline encoded, and often autoreactive. In the case of B cells they appear to use a distinct immune recognition strategy during developmental selection and functional activation. These B cells respond to foreign antigens, and have the ability to protect against a variety of infections; however, they can also react with self or neoself antigens. They appear to use the latter as positively selecting ligands facilitating their entry into and maintenance in a functional repertoire, as well as providing cues for positioning themselves in strategic microenvironmental niches in the immune system and at interfaces with the environment. These innate-like B cell subsets form a bridge between the rapidly occurring innate immune responses, and the slower acting primary, T cell-dependent, adaptive antibody response by providing a rapid T cell-independent antibody response.

Animals↗