摘要:

To provide protection against all foreign pathogens one can possibly encounter during their lifetime, the T cell repertoire has to be as diverse as possible. At the same time, it is desirable that the T cell repertoire remains unresponsive towards healthy tissues. To realize this self/nonself discriminatory property, T cells undergo tightly controlled selection processes during maturation in the thymus. The key parameter determining the outcome of these selection processes is the avidity of the T cells for self-MHC/self-peptide complexes expressed in the thymus; low avidity interactions result in positive selection, whereas high avidity interactions lead to negative selection. Despite the selection processes, self-tolerance is far from absolute. In many cases, this is due to the presence of self-antigen in the thymus at a level that is too low to induce thymic deletion. In addition, T cells with a low avidity for ubiquitously expressed self-antigens can escape clonal deletion and enter the periphery. A thorough understanding of the self-specific T cell repertoire is important because many potential targets for cancer immunotherapy are self-proteins. In this review, the authors discuss the impact of self-antigen expression on the CD8+T cell repertoire. An overview of the fate and functional capacities of self-specific T cells with specificity for tissue-restricted self-antigens and for ubiquitously expressed self-antigens is provided. Furthermore, the authors discuss the influence of negative selection on the antitumor reactivity of the mature T cell repertoire.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Autoantibodies to surface molecules on lymphocytes have already been described in various immune conditions, such as, autoimmune diseases, infections, and blood transfusions. Because T-cell costimulatory molecules play a central role in the immune response of T-cells, we investigated the presence of autoantibodies against T-cell costimulatory molecules in canine autoimmune diseases. In this study, we prepared recombinant proteins of CTLA-4 (CD152) and CD28 and investigated the presence of autoantibodies against them in serum samples obtained from dogs with various autoimmune diseases and from healthy dogs as controls, using the recombinant GST fusion proteins by ELISA. Anti-CTLA-4 antibodies were found in 31.8% of patients with rheumatoid arthritis, 20% of patients with systemic lupus erythematosus, 12.5% of patients with pemphigus, 0% of patients with immune-mediated hemolytic anemia, and 0% of healthy donors. Anti-CD28 antibodies were not found in any of the patients or healthy donors. The ELISA results were further confirmed by immunoblotting. The presence of anti CTLA-4 antibodies suggests the existence of a CTLA-4-specific immune response. The autoantibodies against CTLA-4, demonstrated here for the first time in canine autoimmune diseases, may modulate the immune response in dogs with autoimmune diseases.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The authors studied the combined effects of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-2 on the functions and antitumor activity of natural killer (NK) 1.1+cells in vitro and in vivo. NK1.1+cells were isolated from the spleen of mice treated with saline or M-CSF, and their functions (proliferation, production of IFN-&ggr;, and cytotoxicity) evaluated in vitro. Although the proliferation of and production by NK1.1+cells was stimulated by the addition of IL-2, the cells from the M-CSF-treated mice responded better. Furthermore, the cytotoxicity against Yac-1 cells and B16 melanoma cells was stimulated by M-CSF administration and enhanced by the addition of IL-2 and IL-12. These results demonstrated that M-CSF treatment augmented the functions of NK1.1+cells, and IL-2 and IL-12 boosted these activities in vitro. The authors then examined the effects of co-administration of M-CSF and IL-2 in vivo. The clearance of B16 cells in lung was augmented by the administration of M-CSF but not IL-2. However, M-CSF + IL-2 treatment further enhanced the clearance activity. The anti-metastatic activity was also enhanced by the M-CSF + IL-2 treatment. Furthermore, the survival of B16-bearing mice was prolonged by M-CSF + IL-2. These results suggested that administration of IL-2 boosts the functions of NK1.1+cells, which are augmented preliminarily by the administration of M-CSF.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The authors previously showed that C34+progenitor cells are mobilized into the peripheral blood in tumor bearers. The current study used a murine Lewis lung carcinoma (LLC) model to examine if the CD34+cells can be chemoattracted to a tumor excision site as the first step to inducing differentiation of the attracted CD34+cells into immune stimulatory dendritic cells (DC). Upon tumor excision, gelatin sponges were implanted into the surgical site and infused with phosphate-buffered saline or vascular endothelial cell growth factor (VEGF). The implants were removed after 4, 7, 14, and 21 days and analyzed for their cellular content. The incorporation of VEGF into implants increased the accumulation of CD34+cells early after implantation. By day 21, the CD34+cell content declined. However, the numbers of DCs became increased in the VEGF-containing sponges and this persisted throughout the 3-week duration of the study. The VEGF-containing implants contained a lower percentage of CD11b+myeloid cells for the first 2 weeks after implantation as compared with the control implants. By 21 days, myeloid cell numbers declined in the control and VEGF implants. Since endothelial cell precursors have a common precursor with myeloid progenitor cells, the implants were also examined for their endothelial cell content. With increasing time after implantation, the number of endothelial cells and formation of vessel-like structures became greater in the VEGF-containing implant as compared with the control implants. These results show the feasibility of using VEGF-containing sponges to attract DC precursors and to increase the number of DCs at the tumor excision site.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The use of appropriate antigenic peptides for the most common human major histocompatibility complex (MHC) alleles is required for the amplification of the autologous cytotoxic compartment and the development of cytotoxic T cell-mediated immunity. The human A2 allele of the MHC plays an important role for the identification of peptide-specific cytotoxic T cells (CTL) against tumor and viral epitopes. Computer-based prediction algorithms, which are available on the Internet, have already proved to be applicable for the identification of novel CTL epitopes. Using the bioinformatics approach, the authors have identified the novel influenza matrix protein-derived and HLA-A3-restricted 9-mer peptide RLEDVFAGK capable of inducing peptide specific CTL reactivity. Peripheral blood mononuclear cells (PBMC) from healthy individuals and patients with lung cancer were pulsed with this peptide and with the well-characterized HLA-A2-restricted influenza A virus matrix peptide58–66GILGFVFTL. Using quantitative PCR (TaqMan; Applied Biosystems, Foster City, CA, U.S.A), reactivity for both peptides was determined by measuring the change in type 1 cytokine (IFN-&ggr;) expression upon in vitro stimulation. Peptide-specific reactivity matched well with the subsequently determined MHC-class I alleles of the tested individuals. Results from this study indicate that the use of bioinformatics and the PCR-based screening system for the monitoring of T cell reactivity may allow for the identification of novel CTL epitopes.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-&ggr;, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-&bgr;2, and decrease in IFN-&ggr; -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The authors have investigated a new way of combining cytokines with tumor cells to prepare anticancer vaccines. This method may offer an alternative to gene therapy approaches. It consists in anchoring recombinant cytokines to the cell membrane. Attachment is mediated by the transmembrane domain of diphtheria toxin (T) genetically fused to the cytokine and is triggered by an acid pH pulse. The authors found that the fusion protein T-hIL-2 anchored to the surface of tumor cells retained its IL-2 activity while remaining exposed for several days. Interestingly, vaccination of mice with these modified tumor cells induced a protective antitumor immunity mediated by tumor-specific cytotoxic T lymphocytes. This procedure presents several advantages as compared with the conventional approaches based on the transfection of tumor cells with cytokine genes. It does not require the culture of tumor cells from the patients and the selection of transfected clones, it eliminates the safety problems connected with viral vectors, and it allows the control of the amount of cytokines delivered with the vaccine.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Dendritic cells (DCs) can be matured by CD40 stimulation to upregulate their MHC class II/peptide complexes and costimulatory molecule surface expression to become adept at presenting antigen to and activating naive T lymphocytes. The use of anti-CD40 antibodies as adjuvants for DC-based therapy has been advanced. Little is known as to how DC biology in response to CD40 ligation differs between in vitro versus in vivo ligation. Therefore, the authors analyzed the expression kinetics of MHC class II (I-Ak)/HEL peptide “complex,” total MHC class II, CD80, and CD86 on in vitro or in vivo CD40-stimulated DCs over a period of 5 days. MHC class II, “complex,” and costimulatory molecule expression was elevated at 1 day in vitro and stayed high for the culture period, whereas in vivo expression of the cohort of molecules peaked earlier and then declined. When purified DCs were co-cultured in vitro with antigen-specific T cell hybridomas, the DCs had lower expression of total MHC class II and “complex,” but did not reduce their CD80 and CD86 expression. The lower expression was dependent on cognate interaction as a non-antigen-specific T cell hybridoma was without effect. Blocking antigen-specific MHC class II/peptide-T cell receptor (TcR) complex interaction with antibody inhibited the reduction of MHC class II expression on CD40-stimulated DCs in vitro. Overall, their studies suggest distinct response of DCs to typical conditions that feature anti-CD40 monoclonal antibody (mAb)-activated DCs in vitro or in vivo.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Murine studies have suggested that a population of CD4+T cells expressing the alpha chain of the interleukin (IL)-2 receptor (CD25+) are phenotypically anergic in response to T cell receptor stimulation and can suppress the function of CD4+and CD8+T cells. Recent studies of peripheral lymphocytes from healthy human volunteers have identified a similar population, although little is known about the presence and activity of these cells in patients with cancer and their possible impact on anticancer immunization strategies. Thus, the authors have undertaken these studies in patients with metastatic melanoma undergoing immunizations with known melanoma antigens. CD4+CD25+, CD4+CD25−, and a 1:1 ratio of these isolated T cells were stimulated with soluble anti-CD3 antibody in the presence of irradiated T cell-depleted PBMCs, and proliferation was assessed by measuring [3H]thymidine incorporation. In 13 patients, isolated CD4+CD25+T cells proliferated 68% (± 5.8%) less than separately cultured CD4+CD25−T cells. Moreover, CD4+CD25+T cells suppressed the proliferation of an equal number of cocultured CD4+CD25+T cells in 11 of 13 patients by an average of 60% (± 4.9%). Suppression was not seen at day three of culture and became apparent at days five through nine. The degree of suppression was proportional to the numbers of CD4+CD25+T cells. Addition of high-dose IL-2 reversed the hypoproliferative phenotype of the CD4+CD25+T cells and abrogated their suppressive function. These studies demonstrate that anergic and functionally suppressive CD4+CD25+T cells exist in patients with melanoma undergoing tumor antigen immunization and thus may play a role in modifying the magnitude of the T cell response to immunization.

ISSN:1524-9557    

出版商:OVID    

年代:2003

数据来源: OVID