CD4 T-Helper Responses to the ALK Protein in Patients with ALK-Positive ALCL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3352-3352
Author(s):  
Kamel K. Ait-Tahar ◽  
Chris S.R. Hatton ◽  
Karen K. Pulford
Keyword(s):  
T Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Immune Recognition ◽  
T Helper ◽  
Healthy Donors ◽  
Irrelevant Peptide ◽  
Ifn Γ ◽  
Alk Positive ◽  
Alk Protein

Abstract Anaplstic Lymphoma Kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) has a favourable prognostic outlook compared to ALK-negative AlCL, possibly as a result of the immune recognition of the ALK protein. We have previously shown the presence of both a cytotoxic T cell and an antibody response to the ALK protein in patients with ALK-positive ALCL. The aim of our present study was to investigate the presence of a CD4 T-helper (Th) response in patients with ALK-positive ALCL and in control individuals. Using the TEPITOPE web-based predicitive search algorithm, three 24-mer promiscuous peptides were identified from the ALK sequence as being potentially immunogenic in the context of MHC class II. A gamma-interferon (γ-IFN) and IL-4 ELISPOT assay was used to detect a T cell response in the peripheral blood cells from patients with ALK-positive and ALK- negative ALCL, as well as healthy controls after 6–11 days of culture with the three peptides. ALK278–301 and ALK233–256 were shown to be highly immunogenic in the majority of the ALK-positive patients (see Table). ALK411–434 was immunogenic to T cells from only one of the ALK-positive patients (Patient 4). Cells from none of the two ALK-negative ALCL patients or the five healthy donors showed any reactivity to the ALK peptides. No response to the control irrelevant peptide was observed in any of the ALCL patients or healthy donors. With the exception of one ALK-positive ALCL patient (Patient 2), no significant IL-4 response was recorded in any of the patients or controls. All of the ALK-positive patients presented antibodies to the ALK protein at time of diagnosis.These findings further demonstrate the immunogenicity of the ALK protein and are suggestive of a Th1 type of immune response to the protein. Our findings are of potential prognostic value and open up therapeutic options for those ALK-positive patients who do not respond well to chemotherapy. Summary of the CD4 Th responses to ALK in ALCL patients and healthy donors None PHA (10 μ g/ml) ALK233–256 (10 μM)- (IFN- γ/IL-4) ALK278–301(10 μM)- (IFN- γ/IL-4) ALK411–434 (10 μM)- (IFN- γ/IL-4) Irrelevant peptide (10 μM)- (IFN- γ) Antibody titres to ALK (IgG isotype) ND= Not done. Results are of triplicate cultures ALK+ve patients Patient 1 12 188 56/10 44/18 22/6 8 1/2250 Patient 2 20 240 126/48 78/52 40/26 18 1/2250 Patient 3 14 48 38/ND 24/ND 12/ND 16 1/6750 Patient 4 6 108 64/8 72/8 22/6 10 1/60750 Patient 5 10 48 36/13 26/18 12/12 14 1/6750 Patient 6 15 132 74/ND 58/ND 28/ND 18 1/6750 Patient 7 10 180 34/28 56/32 12/9 12 1/750 ALK-ve patients Patient 8 14 122 12/10 10/6 12/14 22 −ve Patient 9 16 82 14/ND 12/ND 10/ND 24 −ve Healthy Donors Normal 1 22 148 18/14 22/24 26/12 10 −ve Normal 2 12 18 2/4 6/8 12/2 4 −ve Normal 3 10 38 12/10 12/16 9/4 18 −ve Normal 4 9 172 9/ND 10/ND 6/ND 12 −ve Normal 5 4 108 8/12 8/12 2/1 10 −ve

scholarly journals T-Cell Epitopes in Severe Acute Respiratory Syndrome (SARS) Coronavirus Spike Protein Elicit a Specific T-Cell Immune Response in Patients Who Recover from SARS

2004 ◽  
Vol 78 (11) ◽  
pp. 5612-5618 ◽  
Author(s):  
Yue-Dan Wang ◽  
Wan-Yee Fion Sin ◽  
Guo-Bing Xu ◽  
Huang-Hua Yang ◽  
Tin-yau Wong ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
T Cell Response ◽  
Cell Immune Response ◽  
T Cell Epitopes ◽  
Online Database ◽  
Database Analysis ◽  
S Protein ◽  
Healthy Donors ◽  
Ifn Γ

ABSTRACT The immunogenicity of HLA-A2-restricted T-cell epitopes in the S protein of the Severe acute respiratory syndrome coronavirus (SARS-CoV) and of human coronavirus strain 229e (HCoV-229e) was analyzed for the elicitation of a T-cell immune response in donors who had fully recovered from SARS-CoV infection. We employed online database analysis to compare the differences in the amino acid sequences of the homologous T epitopes of HCoV-229e and SARS-CoV. The identified T-cell epitope peptides were synthesized, and their binding affinities for HLA-A2 were validated and compared in the T2 cell system. The immunogenicity of all these peptides was assessed by using T cells obtained from donors who had fully recovered from SARS-CoV infection and from healthy donors with no history of SARS-CoV infection. HLA-A2 typing by indirect immunofluorescent antibody staining showed that 51.6% of SARS-CoV-infected patients were HLA-A2 positive. Online database analysis and the T2 cell binding test disclosed that the number of HLA-A2-restricted immunogenic epitopes of the S protein of SARS-CoV was decreased or even lost in comparison with the homologous sequences of the S protein of HCoV-229e. Among the peptides used in the study, the affinity of peptides from HCoV-229e (H77 and H881) and peptides from SARS-CoV (S978 and S1203) for binding to HLA-A2 was higher than that of other sequences. The gamma interferon (IFN-γ) release Elispot assay revealed that only SARS-CoV-specific peptides S1203 and S978 induced a high frequency of IFN-γ-secreting T-cell response in HLA-A2+ donors who had fully recovered from SARS-CoV infection; such a T-cell epitope-specific response was not observed in HLA-A2+ healthy donors or in HLA-A2− donors who had been infected with SARS-CoV after full recovery. Thus, T-cell epitopes S1203 and S978 are immunogenic and elicit an overt specific T-cell response in HLA-A2+ SARS-CoV-infected patients.

scholarly journals Augmented induction of CD8+ cytotoxic T-cell response and antitumour resistance by T helper type 1-inducing peptide

Immunology ◽  
2006 ◽  
Vol 117 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Takeshi Kikuchi ◽  
Shuichiro Uehara ◽  
Haruyuki Ariga ◽  
Takeshi Tokunaga ◽  
Ai Kariyone ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Helper ◽  
Helper Type

scholarly journals Presentation of the H-Y antigen on Langerhans' cell-negative corneal grafts downregulates the cytotoxic T cell response and converts responder strain mice into phenotypic nonresponders.

1988 ◽  
Vol 168 (5) ◽  
pp. 1749-1766 ◽  
Author(s):  
J S Peeler ◽  
D G Callanan ◽  
M W Luckenbach ◽  
J Y Niederkorn
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Langerhans Cells ◽  
Antigen Expression ◽  
T Cell Response ◽  
T Helper Cell ◽  
Cytotoxic T Cell ◽  
T Helper ◽  
Active Suppression

We have used the murine cornea is an allograft model to investigate the relative roles of graft-derived IA+ APC (Langerhans' cells) and host-derived APC during the induction of CTL responses to H-Y. The natural exclusion of LC from the immunizing corneal graft led to a specific state of unresponsiveness to H-Y in responder strain mice, while inclusion of LC resulted in responsiveness. Failure to respond to H-Y could not be attributed to the absence of H-Y or IA antigen expression on the surface of LC-deficient grafts but instead, appeared to be due to active suppression of the T helper cell response during in vivo priming. Reprocessing of the H-Y antigen by host APC did not occur after immunization with H-Y presented on H-2-incompatible grafts unless presented initially by graft-derived LC. H-2 as well as some non-H-2 alloantigens were presented to the host without a requirement for donor-derived LC. Thus there appear to be differential requirements for the processing and presentation of alloantigens.

scholarly journals Ontogeny of cell-mediated immunity. I. Early development of alloantigen-specific cytotoxic T-cell precursors in postnatal mice.

1977 ◽  
Vol 146 (3) ◽  
pp. 887-892 ◽  
Author(s):  
L M Pilarski
Keyword(s):  
T Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Mediated Immunity ◽  
Immune Functions ◽  
T Helper ◽  
Spleen Cells ◽  
Graft Versus Host ◽  
Accessory Cells ◽  
Old Mice

Cytotoxic T-cell precursors have been shown to occur in spleens of 2-3-day-old mice. By 12 days after birth, the cytotoxic T-cell response of spleen cells to alloantigens has reached 23-32% of adult levels. Addition of extra T-helper cells did not permit cytotoxic T-cell development in spleen cells from newborn to 2-day-old mice suggesting either a lack of precursors or suppression of precursors. The ontogeny of cell-mediated immune functions has thus been shown to correlate well with other work on the development of humoral immunity, accessory cells, and graft versus host reactivity.

scholarly journals Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice

2020 ◽  
Author(s):  
Ying Ma ◽  
Kang Tang ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Linfeng Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Challenge Test ◽  
T Cell Response ◽  
Hantaan Virus ◽  
Cytotoxic T Cell ◽  
Epitope Peptide ◽  
Ctl Epitope ◽  
Ifn Γ ◽  
Hla A2.1

Abstract Background: An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed.Methods: Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test.Results: The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could reduce HTNV RNA loads in vivo.Conclusions: This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.

scholarly journals Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Ying Ma ◽  
Kang Tang ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Linfeng Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Challenge Test ◽  
T Cell Response ◽  
Hantaan Virus ◽  
Cytotoxic T Cell ◽  
Epitope Peptide ◽  
Ctl Epitope ◽  
Ifn Γ ◽  
Hla A2.1

Abstract Background An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed. Methods Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test. Results The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could reduce HTNV RNA loads in vivo. Conclusions This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.

scholarly journals Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice

2020 ◽  
Author(s):  
Ying Ma ◽  
Kang Tang ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Linfeng Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Response ◽  
Hantaan Virus ◽  
Cytotoxic T Cell ◽  
Effective Vaccine ◽  
Epitope Peptide ◽  
Ctl Epitope ◽  
Ifn Γ ◽  
Hla A2.1

Abstract Background An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed.Methods Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test.Results The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could inhibit HTNV replication in vivo.Conclusions This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.

scholarly journals Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice

2020 ◽  
Author(s):  
Ying Ma ◽  
Kang Tang ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Linfeng Cheng ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Challenge Test ◽  
T Cell Response ◽  
Hantaan Virus ◽  
Cytotoxic T Cell ◽  
Epitope Peptide ◽  
Ctl Epitope ◽  
Ifn Γ ◽  
Hla A2.1

Abstract Background: An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed.Methods: Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test.Results: The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could reduce HTNV RNA loads in vivo.Conclusions: This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.

Clinical Grade Generation of T-Helper-1-Driven Polyclonal T-Cell Populations for Adoptive Immunotherapy Against Tumor Associated Antigens

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4314-4314
Author(s):  
Simone Kayser ◽  
Cristina Boß ◽  
Vanya Icheva ◽  
Stefan Stevanovic ◽  
Peter Lang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Peripheral Blood ◽  
Adoptive T Cell Therapy ◽  
T Helper ◽  
T Cell Therapy ◽  
Tumor Associated Antigens ◽  
Healthy Donors ◽  
Ifn Γ

Abstract Abstract 4314 Adoptive T cell therapy has been shown an option to treat patients with malignancies. In contrast to vaccinations, T cells for adoptive T-cell therapy are generated ex vivo to be re-infused into the recipient. This enables treatment of immunocompromized hosts and use of allogeneic T cells to exploit graft versus tumor effects. Adoptive T-cell therapy involving CD4+ T-helper cells (Th cells), intends to induce sustained T-cell responses in vivo. The Th1 cytokine interferon-gamma (IFN-γ) has not only an effect in orchestrating cytotoxic T-cell reponses, IFN-γ by itself has antitumor effects. Transferring T cells in a lymphopenic host furthermore eliminates regulatory T cells (Tregs) and offers access to homeostatic cytokines. The aim of our study was the translation of preclinical data into a GMP conform clinical scale protocol to generate specific T cells for adoptive T-cell therapy against tumor associated antigens. Large scale generations of NY-ESO-1 specific T cells was performed according to current GMP regulations in a GMP facility. In brief, peripheral blood mononuclear cells from healthy donors were primed with an overlapping NY-ESO-1 15-mer peptide mix. The priming was done in the presence of IL-7 and IL-2. T cells were enriched using IFN-γ capture technique and expanded for two weeks in autologous culture conditions with IL-7, IL-15 and IL-2. T-cell specificity, function and proliferation capacity was analyzed by flow cytometry. The T-cell products showed high numbers of specifically IFN-γ+, TNF-alpha+ T cells. Tolerance inducing cytokines like IL-10 were absent. Enrichment of Tregs was excluded. Both, CD4+ and CD8+ T cells with an effector memory phenotype proliferated in response to NY-ESO-1. CD107a assays demonstrated cytotoxic capacities of T cells. The T-cell product did not include alloreactive T cells. In summary GMP-conform generation of NY-ESO-1 specific T cells was established. Although tumor associated antigens are potential self antigens, it is possible to induce a functional Th1 response in peripheral blood T cells from healthy donors. Adoptive T-cell therapy against tumor associated antigens could have implications for multiple tumor entities in autologous as well as allogeneic treatment approaches. Disclosures: No relevant conflicts of interest to declare.

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