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1.
Insulin-dependent diabetes mellitus (IDDM) develops in nonobese diabetic (NOD) mice through the destruction of the B cells
in pancreatic Langerhans islets by islet autoantigen-specific T cells. The islet autoantigen glutamic acid decarboxylase 65
(GAD65) is thought to be a major target autoantigen in IDDM. In the present report, we established GAD65-specific T-cell clones
using overlapping peptides that cover the amino acid sequences of mouse GAD65. T-cell epitopes of GAD65 were characterized
by proliferation and binding assays using various analogue peptides and wild-type or mutant I-Ag7 transfectants. The efficacy of the peptide vaccine in IDDM was determined by administering T-cell epitope peptides to NOD
mice and evaluating the histopathology of their insulitis. We obtained two types of T-cell clone, one specific for peptide
p316–335 and another specific for p531–545 of GAD65. The p531–545 site has already been identified, but we report the p316–335
site for the first time. T-cell clones recognized those peptides in the wild-type I-Ag7 but not in the mutant I-Ag7 in which the serine at position 57 of the β-chain was replaced by an aspartic acid. Both the p316–335 and p531–545 peptides
bound weakly to I-Ag7. Some peptides with amino acid substitutions had antagonistic activity, and administration of a large amount of wild-type
peptide reduced the severity of insulitis in NOD mice. Our results suggest that peptide vaccine therapy may be useful in autoimmune
diseases, including IDDM.
Received: 19 July 1999 / Revised: 4 January 2000 相似文献
2.
3.
The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole-genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17. For the present study, we have established a panel of new congenic, MHC-recombinant mouse strains bearing differential small segments of chromosome 17 transferred from the TB-susceptible I/St (H2
j) strain onto the genetic background of TB-resistant C57BL/6 (B6) mice (H2
b). This allowed narrowing the QTL interval to 17Ch: 33, 77–34, 34 Mb, containing 36 protein-encoding genes. Cloning and sequencing of the H2
j allelic variants of these genes demonstrated profound polymorphic variations compare to the H2
b haplotype. In two recombinant strains, B6.I-249.1.15.100 and B6.I-249.1.15.139, recombination breakpoints occurred in different sites of the H2-Aβ 1 gene (beta-chain of the Class II heterodimer H2-A), providing polymorphic variations in the domain β1 of the Aβ-chain. These variations were sufficient to produce different TB-relevant phenotypes: the more susceptible B6.I-249.1.15.100 strain demonstrated shorter survival time, more rapid body weight loss, higher mycobacterial loads in the lungs and more severe lung histopathology compared to the more resistant B6.I-249.1.15.139 strain. CD4+ T cells recognized mycobacterial antigens exclusively in the context of the H2-A Class II molecule, and the level of IFN-γ-producing CD4+ T cells in the lungs was significantly higher in the resistant strain. Thus, we directly demonstrated for the first time that the classical H2- Ab1 Class II gene is involved in TB control. Molecular modeling of the H2-Aj product predicts that amino acid (AA) substitutions in the Aβ-chain modify the motif of the peptide–MHC binding groove. Moreover, unique AA substitutions in both α- and β-chains of the H2-Aj molecule might affect its interactions with the T-cell receptor (TCR). 相似文献
4.
S (survivor) mutants were produced in mice for genetic analysis of host resistance to metastatic cancer. S-mutants S-27 and S-31 resist transplantation of lymphoma EL4 of parental C57BL/6J (B6) mice while they accept parental skin grafts. Mutant S-27 also resists formation of spontaneous metastases from intradermally growing EL4 tumor into lymp nodes; mutant S-31 is highly susceptible to EL4 metastases. Another mutant. H-2
bm26 (bm26), resists EL4 and rejects B6 skin grafts. Major histocompatibility complex (MHC) class I and class II gene expression was compared in these mutants and normal B6 mice. All three mutants tested, S-27, S-31, and bm26, expressed a low amount of K
b mRNA in organspecific fashion. Mutant bm26 and S-31 expressed a low amount of Ab
b mRNA and of Ab antigen on their spleen cells. Some oligonucleotide probes designed to hybridize to the second exon of the clss II MHC gene Ab
b did not hybridize with DNA from all three mutants. These findings suggest extensive sequence alternations in the Ab
b gene in mutants S-27, S-31, and bm26; they also suggest a major role of MHC in the control of host resistance to spontaneous metastases of the EL4 tumor.
Address correspondence and offprint request to: I. K.. Egorov. 相似文献
5.
Choisy-Rossi CM Holl TM Pierce MA Chapman HD Serreze DV 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(6):3791-3800
For unknown reasons, the common MHC class I variants encoded by the H2g7 haplotype (Kd, Db) aberrantly elicit autoreactive CD8 T cell responses essential to type 1 diabetes development when expressed in NOD mice, but not other strains. In this study, we show that interactive non-MHC genes allow a NOD-derived diabetogenic CD8 T cell clonotype (AI4) to be negatively selected at far greater efficiency in C57BL/6 mice congenically expressing H2g7 (B6.H2g7). However, the few AI4 T cells escaping negative selection in B6.H2g7 mice are exported from the thymus more efficiently, and are more functionally aggressive than those of NOD origin. This provides mechanistic insight to previous findings that resistant mouse strains carry some genes conferring greater diabetes susceptibility than the corresponding NOD allele. In the B6.H2g7 stock, non-MHC gene-controlled elevations in TCR expression are associated with both enhanced negative selection of diabetogenic CD8 T cells and increased aggressiveness of those escaping this process. An implication of this finding is that the same phenotype, in this case relatively high TCR expression levels, could have double-edged sword effects, contributing to type 1 diabetes resistance at one level of T cell development, but at another actually promoting pathogenesis. 相似文献
6.
Serreze DV Choisy-Rossi CM Grier AE Holl TM Chapman HD Gahagan JR Osborne MA Zhang W King BL Brown A Roopenian D Marron MP 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3250-3259
When expressed in NOD, but not C57BL/6 (B6) genetic background mice, the common class I variants encoded by the H2g7 MHC haplotype aberrantly lose the ability to mediate the thymic deletion of autoreactive CD8+ T cells contributing to type 1 diabetes (T1D). This indicated some subset of the T1D susceptibility (Idd) genes located outside the MHC of NOD mice interactively impair the negative selection of diabetogenic CD8+ T cells. In this study, using both linkage and congenic strain analyses, we demonstrate contributions from a polymorphic gene(s) in the previously described Idd7 locus on the proximal portion of Chromosome 7 predominantly, but not exclusively, determines the extent to which H2g7 class I molecules can mediate the thymic deletion of diabetogenic CD8+ T cells as illustrated using the AI4 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the AI4 clonotypic TCR alpha-chain on developing thymocytes in B6.H2g7 and NOD background mice. This expression difference likely lowers levels of the clonotypic AI4 TCR in NOD, but not B6.H2g7 thymocytes, below the threshold presumably necessary to induce a signaling response sufficient to trigger negative selection upon Ag engagement. These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients. 相似文献
7.
Allogeneic differences in the dependence on CD4+ T-cell help for virus-specific CD8+ T-cell differentiation
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CD4+ T-cell help enables antiviral CD8+ T cells to differentiate into fully competent memory cells and sustains CD8+ T-cell-mediated immunity during persistent virus infection. We recently reported that mice of C57BL/6 and C3H strains differ in their dependence on CD28 and CD40L costimulation for long-term control of infection by polyoma virus, a persistent mouse pathogen. In this study, we asked whether mice of these inbred strains also vary in their requirement for CD4+ T-cell help for generating and maintaining polyoma virus-specific CD8+ T cells. CD4+ T-cell-depleted C57BL/6 mice mounted a robust antiviral CD8+ T-cell response during acute infection, whereas unhelped CD8+ T-cell effectors in C3H mice were functionally impaired during acute infection and failed to expand upon antigenic challenge during persistent infection. Using (C57BL/6 × C3H)F1 mice, we found that the dispensability for CD4+ T-cell help for the H-2b-restricted polyoma virus-specific CD8+ T-cell response during acute infection extends to the H-2k-restricted antiviral CD8+ T cells. Our findings demonstrate that dependence on CD4+ T-cell help for antiviral CD8+ T-cell effector differentiation can vary among allogeneic strains of inbred mice. 相似文献
8.
Genetic control of homeostasis of peripheral CD4+ lymphocyte levels is incompletely understood. Recent genome scans have linked mouse peripheral CD4 levels to chromosome 17, with strongest linkage to the Ea region. Nonobese diabetic (NOD) mice demonstrate peripheral T-cell lymphocytosis, and previous studies also suggested that the MHC region might control this phenotype. Here we confirm that loci on Chr 17 control NOD peripheral CD4 lymphocytosis. An elevated NOD CD4:CD8 ratio maps to the same region, and we show it is due to increased numbers of CD4+ cells. However, using NOD MHC congenic mice, we demonstrate that the MHC region is excluded, and that NOD peripheral lymphocytosis is controlled by genetic intervals adjacent to the MHC region on Chr 17. 相似文献
9.
Serreze DV Holl TM Marron MP Graser RT Johnson EA Choisy-Rossi C Slattery RM Lieberman SM DiLorenzo TP 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(2):871-879
Development of autoreactive CD4 T cells contributing to type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is either promoted or dominantly inhibited by particular MHC class II variants. In addition, it is now clear that when co-expressed with other susceptibility genes, some common MHC class I variants aberrantly mediate autoreactive CD8 T cell responses also essential to T1D development. However, it was unknown whether the development of diabetogenic CD8 T cells could also be dominantly inhibited by particular MHC variants. We addressed this issue by crossing NOD mice transgenically expressing the TCR from the diabetogenic CD8 T cell clone AI4 with NOD stocks congenic for MHC haplotypes that dominantly inhibit T1D. High numbers of functional AI4 T cells only developed in controls homozygously expressing NOD-derived H2(g7) molecules. In contrast, heterozygous expression of some MHC haplotypes conferring T1D resistance anergized AI4 T cells through decreased TCR (H2(b)) or CD8 expression (H2(q)). Most interestingly, while AI4 T cells exert a class I-restricted effector function, H2(nb1) MHC class II molecules can contribute to their negative selection. These findings provide insights to how particular MHC class I and class II variants interactively regulate the development of diabetogenic T cells and the TCR promiscuity of such autoreactive effectors. 相似文献
10.
To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-Ag7 and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-Ag7, which activated autoreactive CD4+ T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-Ag7 RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-Ag7 RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries. 相似文献
11.
Rong Hou Mareki Ohtsuji Li Zhang Takahiro Adachi Sachiko Hirose 《Biochemical and biophysical research communications》2009,380(1):193-197
The nonobese diabetic (NOD) mouse is a useful model of autoimmune type 1 diabetes exhibiting many similarities to human type 1 diabetes patients including the presence of auto-reactive T cells and pancreas-specific autoantiboies. Multiple Idd loci control the development of diabetes in NOD mice. CD72, a B cell membrane-bound glycoprotein carrying a C-type lectin-like domain, is an inhibitory co-receptor of the B cell antigen receptor (BCR) that negatively regulates BCR signaling. Among four known haplotypes of mouse CD72, NOD mice carry the CD72c haplotype, whereas most of the other inbred strains of mice carry either CD72a or CD72b. In this study, we generated congenic NOD.CD72b mice that carry C57BL/6 (B6) mouse-derived centromeric chromosome 4 interval (24-45 cM) surrounding the CD72b locus. Unexpectedly, NOD.CD72b mice were not protected from diabetes, but rather exhibited accelerated development of both insulitis and diabetes. Our result defines novel locus or loci in the vicinity of CD72 gene that negatively control diabetes, indicating that NOD disease is under complex genetic controls of not only Idd genes but also disease-resistant genes. 相似文献
12.
Annemieke Geluk Veena Taneja Krista E. van Meijgaarden René R. P. de Vries Chella S. David Tom H. M. Ottenhoff 《Biotherapy》1998,10(3):191-196
Protective immunity against mycobacteria is dependent on antigen/MHC class II specific, CD4+ Th1 cells. HLA-DR3-restricted Th1 cells respond to a subset of mycobacterial antigens, including the immunodominant hsp65,
and recognize a single epitope in hsp65, notably p1-20. Altered peptide ligands (APL) of p1-20 can inhibit p1-20/hsp65-induced
proliferation of DR3-restricted T cells in an allele specific mannerin vitro. In order to develop a preclinical model in which p1-20 APL can be testedin vivo in the context of HLA, we have used murine class II deficient, HLA transgenic (Ab0) mice, in which all CD4+ T cells are restricted by the tg HLA molecule. BCG-immunized DR3.Ab0 and DQ8.Ab0 mice both responded well to hsp65. Furthermore, DR3.Ab0 mice recognized precisely the same p1-20 epitope as DR3-restricted human T cells, whereas DQ8.Ab0 mice responded to a different set of hsp65 peptides. This shows that (i) the same immunodominant protein and peptide epitope
are recognized by T cells from DR3.Ab0 mice and DR3+ humans and (ii) indicates the major role of HLA-polymorphism in controlling the human T cell response to mycobacterial antigens.
Thus, HLA-transgenic, Ab0 mice provide a novel, preclinical model system to analyze APL and vaccines in the context of HLA polymorphism. 相似文献
13.
Trembleau S Penna G Gregori S Magistrelli G Isacchi A Adorini L 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(12):6748-6755
The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-A(g7) class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamma secretion was induced in CD4(+) cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis. 相似文献
14.
Qiang Wan Rajal Shah Daniel J. McCormick Lesley C. Lomo Alvaro A. Giraldo Chella S. David Y. M. Kong 《Immunogenetics》1999,50(1-2):22-30
Susceptibility to experimental autoimmune thyroiditis (EAT) is linked to H2-A class II genes;k and s haplotypes are susceptible, while b and f are resistant. EAT is inducible with thyroglobulins (Tgs) from several mammalian species which share portions of identical
sequences. But cross-activation and cross-tolerance studies with mouse (m), human (h), and porcine (p) Tg have indicated mTg-unique
T-cell epitope(s), in addition to conserved, in EAT induction. The recent introduction of the HLA-DRB1*0301 (DR3) transgene rendered major histocompatibility complex (MHC) class II-negative (Ab0) mice susceptible to EAT induction by both hTg and mTg, suggesting usage of conserved epitopes. Here, we introduced the H2-Ea
k
transgene into resistant B10 (H2
b
) or Ab0 mice with a defective Ea gene to provide functional surface H2E (b haplotype) expression. Surprisingly, both transgenic strains showed severe inflammation only after hTg, but not mTg, immunization,
although the moderating influence of the A
b
gene in B10 was evident. In proliferative assays, hTg-primed cells did not respond to mTg, nor to conserved 12mer peptides
from three primary hormonogenic sites, two of which can activate T cells for thyroiditis transfer and cytotoxicity. The vigorous
response to hTg stimulation was reduced only by Eβb-specific monoclonal antibody. EAT induction with bovine and pTg showed responses similar to hTg, suggesting thyroiditogenic
epitopes shared with hTg, but not mTg. This is the first demonstration of: (1) nonpermissiveness for EAT induction with mTg,
normally the most thyroiditogenic Tg and the one with unique epitopes for susceptible mice, and (2) the separation of hTg
from mTg in EAT induction in H2-E-transgenic mice.
Received: 15 January 1999 / Revised: 23 April 1999 相似文献
15.
Bijan Raziorrouh Malte Heeg Peter Kurktschiev Winfried Schraut Reinhart Zachoval Clemens Wendtner Martin W?chtler Michael Spannagl Gerald Denk Axel Ulsenheimer Bertram Bengsch Hanspeter Pircher Helmut M. Diepolder Norbert H. Grüner Maria-Christina Jung 《PloS one》2014,9(8)
Background
T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure.Methods
The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production.Results
CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-γ, IL-2 and TNF-α secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control.Conclusion
HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation. 相似文献16.
M A. Gonzalez-Gay E. Zanelli Sanjay D. Khare Christopher J. Krco Marie M. Griffiths Harvinder S. Luthra C. S. David 《Immunogenetics》1996,44(5):377-384
Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar
to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex
(MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Eb
d
transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the
polymorphism of the first domain of the Eβ molecule modulates this protection, and that the presentation of a peptide from
the third hypervariable region of the Eβ chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection
is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection,
our results showed that the H2-E molecule failed to protect B10.RIII (H2r) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Eβd-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Eβ peptides, may play an important role in the T-cell repertoire education and/or modulation of
the T-cell response in the periphery.
Received: 29 May 1996 / Revised: 26 June 1996 相似文献
17.
Hamaï A Duperrier-Amouriaux K Pignon P Raimbaud I Memeo L Colarossi C Canzonieri V Perin T Classe JM Campone M Jézéquel P Campion L Ayyoub M Valmori D 《PloS one》2011,6(6):e21129
The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)− invasive ductal carcinomas of high grade, including both HER2− and HER2+ tumors. In line with these results, we detected ESO expression in 20% of primary HR− BC, including both ESO Ab+ and Ab− patients, but not in HR+ BC. Interestingly, whereas expression levels in ESO+ BC were not significantly different between ESO Ab+ and Ab− patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR− (HER2− or HER2+) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy. 相似文献
18.
19.
Florian Helm Thomas Kammertoens Frank M. Lehmann Andrea Wilke Heiko Bruns Josef Mautner Georg W. Bornkamm Armin Gerbitz 《PloS one》2013,8(10)
Over-expression of the proto-oncogene c-MYC is frequently observed in a variety of tumors and is a hallmark of Burkitt´s lymphoma. The fact that many tumors are oncogene-addicted to c-MYC, renders c-MYC a powerful target for anti-tumor therapy. Using a xenogenic vaccination strategy by immunizing C57BL/6 mice with human c-MYC protein or non-homologous peptides, we show that the human c-MYC protein, despite its high homology between mouse and man, contains several immunogenic epitopes presented in the context of murine H2b haplotype. We identified an MHC class II-restricted CD4+ T-cell epitope and therein an MHC class I-restricted CD8+ T-cell epitope (SSPQGSPEPL) that, after prime/boost immunization, protected up to 25% of mice against a lethal lymphoma challenge. Lymphoma-rejecting animals contained MHC multimer-binding CD8+ cell within the peripheral blood and displayed in vivo cytolytic activity with specificity for SSPQGSPEPL. Taken together these data suggest that oncogenic c-MYC can be targeted with specific T-cells. 相似文献
20.
Mathias Schmaler Maria A. S. Broggi Simona W. Rossi 《Journal of visualized experiments : JoVE》2014,(89)
The study of T cell responses and their consequences during allo-antigen recognition requires a model that enables one to distinguish between donor and host T cells, to easily monitor the graft, and to adapt the system in order to answer different immunological questions. Medawar and colleagues established allogeneic tail-skin transplantation in mice in 1955. Since then, the skin transplantation model has been continuously modified and adapted to answer specific questions. The use of tail-skin renders this model easy to score for graft rejection, requires neither extensive preparation nor deep anesthesia, is applicable to animals of all genetic background, discourages ischemic necrosis, and permits chemical and biological intervention. In general, both CD4+ and CD8+ allogeneic T cells are responsible for the rejection of allografts since they recognize mismatched major histocompatibility antigens from different mouse strains. Several models have been described for activating allogeneic T cells in skin-transplanted mice. The identification of major histocompatibility complex (MHC) class I and II molecules in different mouse strains including C57BL/6 mice was an important step toward understanding and studying T cell-mediated alloresponses. In the tail-skin transplantation model described here, a three-point mutation (I-Abm12) in the antigen-presenting groove of the MHC-class II (I-Ab) molecule is sufficient to induce strong allogeneic CD4+ T cell activation in C57BL/6 mice. Skin grafts from I-Abm12 mice on C57BL/6 mice are rejected within 12-15 days, while syngeneic grafts are accepted for up to 100 days. The absence of T cells (CD3-/- and Rag2-/- mice) allows skin graft acceptance up to 100 days, which can be overcome by transferring 2 x 104 wild type or transgenic T cells. Adoptively transferred T cells proliferate and produce IFN-γ in I-Abm12-transplanted Rag2-/- mice. 相似文献