scholarly journals Designer Glycopeptides for Cytotoxic T Cell–based Elimination of Carcinomas

2004 ◽  
Vol 199 (5) ◽  
pp. 707-716 ◽  
Author(s):  
Yanfei Xu ◽  
Sandra J. Gendler ◽  
Alessandra Franco
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Large Population ◽  
Vaccination Strategy ◽  
Cytotoxic T Cell ◽  
Major Histocompatibility ◽  
Carbohydrate Antigens ◽  
Histocompatibility Complex

Tumors express embryonic carbohydrate antigens called tumor-associated carbohydrate antigens (TACA). TACA-containing glycopeptides are appealing cytotoxic T cell (CTL)-based vaccines to prevent or treat cancer because the same sugar moieties are expressed in a variety of tumors, rendering a vaccination strategy applicable in a large population. Here we demonstrate that by using glycopeptides with high affinity for the major histocompatibility complex and glycosylated in a position corresponding to a critical T cell receptor (TcR) contact, it is possible to induce anti-TACA CTL in vivo. In the current study we show that designer glycopeptides containing the Thomsen-Freidenreich (TF) antigen (β-Gal-[1→3]-α-GalNAc-O-serine) are immunogenic in vivo and generate TF-specific CTL capable of recognizing a variety of tumor cells in vitro including a MUC1-expressing tumor. The fine specificity of the TF-specific CTL repertoire indicates that the TcR recognize the glycosylated amino acid residue together with TF in a conventional major histocompatibility complex class I–restricted fashion. These results have high potential for immunotherapy against a broad range of tumors.

scholarly journals Primary in vitro cytotoxic T cell response to non-major histocompatibility complex alloantigens in normal mice.

1982 ◽  
Vol 156 (2) ◽  
pp. 610-621 ◽  
Author(s):  
S Macphail ◽  
I Yron ◽  
O Stutman
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Calf Serum ◽  
Suppressor Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Mouse Serum ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

We have shown for the first time that it is possible to consistently generate a primary in vitro cytotoxic T cell (Tc) response to non-major histocompatibility complex alloantigens using responder cells from a normal mouse strain. This was achieved by carrying out, in the generating phase, a limiting dilution procedure in which it appears that suppressor cells that inhibit Tc activation or expansion are too dilute to manifest their effect. Moreover, the response was observed in mouse serum-(MS) as well as fetal calf serum- (FCS) supplemented media, an important finding in the light of the anomalous nonspecific effects induced by FCS. The cytotoxic response produced in MS-supplemented media was shown to be highly specific in both the generating and effector phases, whereas the responses in FCS had a strong nonspecific component.

scholarly journals Primary in vitro cell-mediated lympholysis reaction of NZB mice against unmodified targets syngeneic at the major histocompatibility complex.

1978 ◽  
Vol 147 (5) ◽  
pp. 1435-1448 ◽  
Author(s):  
U Botzenhardt ◽  
J Klein ◽  
M Ziff
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell System ◽  
Cytotoxic T Cell ◽  
Mouse Strains ◽  
Major Histocompatibility ◽  
Effector Cells ◽  
Histocompatibility Complex ◽  
2D Strain

T-cell cytotoxicity of NZV mice was tested after in vitro sensitization against a group of H-2 identical strains (BALB/c, B10.D2, DBA/2, HW19). A highly significant and unexpected unidirectional cell-mediated lympholysis (CML) reaction by the sensitized NZB effector cells on these targets was found. After sensitization in vitro with stimulator cells of one H-2d strain, NZB effector cells (H-2d) lysed all other H-2d targets and to a lesser degree, some non-H-2d targets (C57BL/10, DBA/1, B10.Q, CBA, B10.S, A.SW). NZB targets were not lysed. Differences in the major histocompatibility region between NZB and other H-2d strains could be excluded as a possible explanation for the observed reaction of NZB (H-2d) against other H-2d strains. These results consequently represent the first description of a primary in vitro CML directed against determinants not coded for in the major histocompatibility complex. The responsible effector cells are demonstrated to be T cells. The CML of NZB against H-2 identiical targets appears best explained by a reaction against minor histocompatibility antigens. This, and the observed cross-reactions, would indicate that the cytotoxic T-cell system in NZB mice is not subjected to restrictions found in all normal mouse strains tested until now under similar conditions. It is suggested that this hyperreactivity is related to the autoimmune responsiveness of the NZB strain.

scholarly journals Role of the major histocompatibility complex in T cell activation of B cell subpopulations. lyb-5(+) and lyb-5(-) B cell subpopulations differ in their requirement for major histocompatibility complex-restricted T cell recognition

1981 ◽  
Vol 154 (2) ◽  
pp. 501-516 ◽  
Author(s):  
A Singer ◽  
PJ Morrissey ◽  
KS Hathcock ◽  
A Ahmed ◽  
I Scher ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Recognition ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Cell Subpopulations

This report has examined the requirements for T helper (T(H)) cell recognition of major histocompatibility complex (MHC) determinants expressed by B cells for the activation of unprimed Lyb-5(+) and Lyb-5(-) B cell subpopulations . The generation of primary T(H) cell-dependent plaque-forming cell responses in vitro microculture required the presence of Lyb-5(+) B cells because B cell populations that were deprived, either genetically or serologically, of the Lyb-5(+) subpopulation were not activated in these responses. Cell-mixing experiments in which A X B {arrow} A chimeric T(H) cells were mixed with purified populations of parental accessory cells and parental B cells demonstrated that the in vitro activation of Lyb-5(+) B cells did not require T(H) cell recognition of B cell MHC determinants, although it did require T(H) cell recognition of accessory cell MHC determinants . In contrast to the failure of Lyb-5(-) B cells to be activated in primary T(H) cell-dependent responses in vitro microculture, isolated populations of Lyb-5(-) B cells were triggered by T(H) cells in vivo in short-term adoptive transfer experiments . By the use of A X B {arrow} A chimeric T(H) cells and parental strain B adoptive hosts, it was possible in vivo to distinguish genetically restricted T(H) cell recognition of B cells from genetically restricted T(H) cell recognition of accessory cells. Similar to the results obtained in vitro, the activation in vivo of unfractionated (Lyb-5(+) plus Lyb-5(-)) B cell populations did not require T(H) cell recognition of B cell MHC determinants . In contrast, in the same in vivo responses activation of isolated populations of Lyb-5(-) B cells did require T(H) cell recognition of B cell MHC determinants. The most straightforward interpretation of these experiments is that T(H) cell recognition of B cell MHC determinants is required for the activation of Lyb-5(-) B cells but is not required for the activation of Lyb-5(+) B cells . To better understand why T(H) cell activation of one B cell subpopulation is genetically restricted, whereas activation of another subpopulation is not, the response of Lyb-5(+) and Lyb-5(-) B cells to the soluble activating factors present in concanavalin A-induced spleen cell supernates (Con A SN) was examined. It was observed that Lyb-5(-) B cells, as opposed to Lyb-5(+) B cells, were unable to respond in microculture to the nonspecific T(H) cell- activating factors present in Con A SN, even though they were able to nonspecifically respond under the same conditions to trinitrophenyllipopolysaccharide. It was observed that the ability of B cell subpopulations to respond to nonspecific soluble T cell factors paralleled their ability to be activated by T(H) cells in a genetically unrestricted manner. Thus, the present experiments demonstrate that activation by T(H) cells of Lyb-5(-) B cells is MHC restricted, whereas activation of Lyb-5(+) B cells is not. These experiments suggest that one possible explanation for such differences is that activation of Lyb-5(+) B cells does not require direct interaction with T(H) cells because they can be activated by soluble activation signals that T(H) cells secrete.

scholarly journals Antigen recognition by a T cell clone outside the context of the major histocompatibility complex. A role for Mls in antigen presentation.

1984 ◽  
Vol 159 (1) ◽  
pp. 305-312 ◽  
Author(s):  
S J Waters ◽  
S D Waksal ◽  
G P Norton ◽  
C A Bona
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Clone ◽  
Antigen Recognition ◽  
Major Histocompatibility ◽  
Spleen Cells ◽  
Differentiation Markers ◽  
Histocompatibility Complex ◽  
T Cell Clone

A T cell clone isolated from antigen-primed CB6/F1 mice was shown to proliferate to keyhole limpet hemocyanin (KLH) in the presence of irradiated syngeneic F1 spleen cells, as well as spleen cells from either parental strain (BALB/c and C57BL/6). The genetic restriction involved in this antigen-specific proliferation was mapped using BXD (C57BL/6 X DBA/2) recombinant inbred strains of mice to the Mls gene on chromosome one. To exclude the role of Ia antigens as the restricting determinants, monoclonal anti-Ia antibodies were used to block the in vitro proliferative response of this clone. Although anti-Iab and anti-Iad blocked the proliferation of this clone to KLH in the presence of irradiated spleen cells from either parent, this effect was shown to be dependent on Ia molecules passively absorbed by the T cell clone from the irradiated filler cells. Since the T clone expressed Thy-1.2 and Lyt-1+ differentiation markers, its helper activity was compared with other KLH carrier-specific clones in an in vitro antibody synthesis assay. The Mls-KLH-restricted T cell clone, in contrast to other carrier-specific, major histocompatibility complex (MHC)-restricted T cell clones, was unable to cooperate with trinitrophenyl (TNP)-primed B cells in the presence of TNP-KLH to generate an anti-TNP response. These experiments suggest that non-MHC determinants, such as autologous Mls gene products, may play a role in genetically restricted antigen recognition by T lymphocytes.

Abstract 124: Parthenogenetic Stem Cell-derived Cardiomyocytes Express Major Histocompatibility Complex-I only after Inflammatory Stimulation

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Satish Galla ◽  
Michael Didie ◽  
Vijayakumar Muppala ◽  
Ralf Dressel ◽  
Wolfram Hubertus Zimmermann
Keyword(s):  
Major Histocompatibility Complex ◽  
Heart Muscle ◽  
Immunological Response ◽  
Type I ◽  
Major Histocompatibility ◽  
Adrenergic Stimulation ◽  
Mhc I ◽  
Histocompatibility Complex

Background: Pluripotent parthenogenetic stem cells (PSCs) can be directed towards a cardiac fate and utilized in tissue engineered heart repair. In vivo applications of tissue engineered allografts are compromised by expression of mismatching major histocompatibility complex proteins (MHC; encoded in the murine H2 locus). Here we investigated whether PSC-derived cardiomyocytes (CM) express MHC-I. Methods: Mouse PSCs (A3-line from B6D2F1 strain with haploidentical H2K d -locus) expressing a CM-specific neomycin-resistance and GFP were differentiated and purified for CM by addition of G418 (85% purity by FACS for actinin). To simulate heart muscle biology in vitro, we made use of engineered heart muscle (EHM) constructed from PSC-derived CM (75%), growth-inhibited murine embryonic fibroblasts (MEF (25%); NMRI mice), and collagen type I. MHC class-I H2K d (MHC-I) expression was assessed on CM and Non myocytes before EHM assembly and from enzymatically digested EHMs (cultured for 10 days) by FACS. Interferon gamma (IFNγ) was added for 48 h to stimulate MHC-I expression. As a reference, we investigated MHC-I expression in CM from neonatal mice and adult mouse hearts by FACS and by immunofluorescence staining. Results: EHM showed a positive ionotropic response to beta-adrenergic stimulation which could be reduced by muscarinergic stimulation. A3-CM, in contrast to Non myocytes, showed negligible expression of MHC-I (1±0.5% vs. 60±10% positive cells; n=3). EHM culture did not change MHC-I expression in CM. IFNγ treatment resulted in a marked increase of MHC-I-expression in CM monolayer culture (40±6%; n=3) and in EHM (30±8%; n=3). For comparison, 30% (n=2) neonatal CM expressed MHC-I while MHC-I was not detectable in adult CM. Conclusion: PSC-derived CM show a similarly low expression of MHC-I as adult CM and respond with MHC-I upregulation to IFNγ stimulation. This suggests a mature immunological response in PSC-CM with important implications for in vivo applications, i.e., MHC-I matching will likely be a prerequisite for successful allografting of PSC-EHM.

scholarly journals Major Histocompatibility Complex Haplotype Determines hsp70-Dependent Protection against Measles Virus Neurovirulence

2009 ◽  
Vol 83 (11) ◽  
pp. 5544-5555 ◽  
Author(s):  
Thomas Carsillo ◽  
Mary Carsillo ◽  
Zachary Traylor ◽  
Päivi Rajala-Schultz ◽  
Phillip Popovich ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Measles Virus ◽  
Protective Role ◽  
Major Histocompatibility ◽  
Major Histocompatibility Complex Haplotype ◽  
Brain Infection ◽  
Histocompatibility Complex ◽  
The Impact

ABSTRACT In vitro studies show that hsp70 promotes gene expression for multiple viral families, although there are few reports on the in vivo significance of virus-hsp70 interaction. Previously we showed that hsp70-dependent stimulation of Edmonston measles virus (Ed MeV) transcription caused an increased cytopathic effect and mortality in transgenic hsp70-overexpressing C57BL/6 mice (H-2 b ). The response to MeV infection is influenced by the major histocompatibility complex haplotype; H-2 d mice are resistant to brain infection due to robust antiviral immune responses, whereas H-2 b mice are susceptible due to deficiencies in this response. We therefore tested the hypothesis that the outcome of MeV-hsp70 interaction may be dependent upon the host H-2 haplotype. The impact of selective neuronal hsp70 overexpression on Ed MeV brain infection was tested with congenic C57BL/10 H-2 d neonatal mice. In this context, hsp70 overexpression conferred complete protection against virus-induced mortality, compared to >30% mortality in nontransgenic mice. Selective depletion of T-cell populations showed that transgenic mice exhibit a diminished reliance on T cells for protection. Brain transcript analysis indicated enhanced innate immune activation and signaling through Toll-like receptors 2 and 4 at early times postinfection for transgenic infected mice relative to those for nontransgenic infected mice. Collectively, results suggest that hsp70 can enhance innate antiviral immunity through Toll-like receptor signaling, supporting a protective role for physiological responses that enhance tissue levels of hsp70 (e.g., fever), and that the H-2 haplotype determines the effectiveness of this response.

scholarly journals Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone.

1992 ◽  
Vol 176 (3) ◽  
pp. 667-677 ◽  
Author(s):  
M H Wauben ◽  
C J Boog ◽  
R van der Zee ◽  
I Joosten ◽  
A Schlief ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility ◽  
In Vitro Proliferation ◽  
Histocompatibility Complex ◽  
Disease Induction ◽  
Immunomodulatory Peptides ◽  
Peptide Analogues

Peptide analogues of disease-associated epitopes were studied for inhibition of experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rats. EAE- and AA-associated analogues were selected as competitors because of their in vitro inhibitory activity on proliferation of encephalitogenic and arthritogenic T cells. Although the EAE-associated competitor had a superior major histocompatibility complex (MHC) binding affinity, the AA-associated competitor was a better inhibitor of the in vitro proliferation of arthritogenic T cells. Furthermore, although in vivo EAE was inhibited by both competitors, AA was only inhibited by the AA-associated competitor. Remarkably, in contrast to what was expected of a regular MHC competitor peptide, the AA-associated peptide analogue also prevented AA upon immunization before disease induction and appeared to induce T cell responses that crossreacted with the original disease-associated epitope. Therefore, it is concluded that antigen-specific regulatory mechanisms were involved in synergy with MHC competition. The integration of both qualities into a single "competitor-modulator" analogue peptide may lead to the development of novel, more effective, disease-specific immunomodulatory peptides.

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