Hybrids of Dendritic Cells and Tumor Cells Generated by Electrofusion Simultaneously Present Immunodominant Epitopes from Multiple Human Tumor-Associated Antigens in the Context of MHC Class I and Class II Molecules

Three new lymphoid tumors offering an assortment of variants in terms of MHC class I expressions, MHC class II expression, and Ig gene transcription have been discovered in the amphibianXenopus. One was developed in an individual of the isogenic LG15 clone (LG15/0), one in a frog of the LG15/40 clone (derived from a small egg recombinant of LG15), and one (ff-2) in a maleffsib of the individual in which MAR1, the first lymphoid tumor in Xenopus was found 2 years ago. These tumors developed primarily as thymus outgrowths and were transplantable in histocompatible tadpoles but not in nonhistocompatible hosts. Whereas LG15/0 and LG15/40 tumor cells also grow in adult LG15 frogs, theff-2 tumor, like the MAR1 cell line, is rejected by adultffanimals. Using flow cytometry with fluorescence-labeled antibodies and immunoprecipitation analysis, we could demonstrate that, like MAR1, these three new tumors express on their cell surface lymphopoietic markers recognized by mAbs FIF6 and RC47, as well as T-cell lineage markers recognized by mAbs AM22 (CD8-1ike) and X21.2, but not by immunologobulin (Ig) nor MHC class II molecules. Another lymphocyte-specific marker AM15 is expressed by 15/0 and 15/40 but notff-2 tumor cells. Theff-2 tumor cell expresses MHC class molecule in association withβ2-microglobulin on the surface, 15/40 cells contain cytoplasmic Iαchain that is barely detected at the cell surface by fluocytometry, and 15/0 cells do not synthesize class Iαchain at all. The three new tumors all produce large amounts of IgM mRNA of two different sizes but no Ig protein on the membrane nor in the cytoplasm. All tumor cell types synthesize large amount of Myc mRNA and MHC class I-like transcripts considered to be non classical.

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MHC class I and class II presentation of tumor antigen in retrovirally and adenovirally transduced dendritic cells

Cancer Gene Therapy ◽

10.1038/sj.cgt.7700509 ◽

2002 ◽

Vol 9 (11) ◽

pp. 946-950 ◽

Cited By ~ 18

Author(s):

J Mark Sloan ◽

Michael H Kershaw ◽

Christopher E Touloukian ◽

Rejean Lapointe ◽

Paul F Robbins ◽

...

Keyword(s):

Dendritic Cells ◽

Mhc Class I ◽

Tumor Antigen ◽

Class Ii ◽

Class I

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Mature dendritic cells pulsed with freeze–thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4+ and CD8+ T lymphocyte responses

Blood ◽

10.1182/blood.v96.5.1857 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1857-1864 ◽

Cited By ~ 91

Author(s):

Wolfgang Herr ◽

Elena Ranieri ◽

Walter Olson ◽

Hassane Zarour ◽

Loreto Gesualdo ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mhc Class I ◽

T Cell Responses ◽

Class Ii ◽

Interferon Γ ◽

Class I ◽

Freeze Thaw ◽

Cell Responses

Abstract Immunotherapy trials targeting the induction of tumor-reactive T-cell responses in cancer patients appear to hold significant promise. Because nonmutated lineage-specific antigens and mutated idiotypic antigens may be coexpressed by tumor cells, the use of autologous tumor material to promote the broadest range of antitumor T-cell specificities has significant clinical potential in cancer vaccination trials. As a model for vaccination in the cancer setting, we chose to analyze the promotion of T-cell responses against Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell line (B-LCL)–derived antigens in vitro. A series of bulk antigenic formats (freeze–thaw lysate, trifluoroacetic acid lysate, extracted membranes, affinity-purified MHC class I– and class II–presented peptides, acid-eluted peptides) prepared from EBV B-LCLs were tested for their ability to stimulate EBV B-LCL–reactive CD4+ and CD8+ T lymphocytes in vitro when pulsed onto autologous dendritic cells (DCs). DC presentation of freeze–thaw lysate material derived from (either autologous or allogeneic) EBV B-LCLs with an Mr of 10 kd or larger stimulated optimal anti-EBV B-LCL responsiveness from freshly isolated CD4+ and CD8+ peripheral blood T cells. These in vivo “memory” T-cell responses were observed only in EBV-seropositive donors. CD4+ T-cell responses to lysate-pulsed DCs were Th1 type (ie, strong interferon-γ and weak interleukin-5 responses). While CD8+ T-cell responses were also observed in interferon-γ Elispot assays and in cytotoxicity assays, these responses were of low frequency unless the DC stimulators were induced to “mature” after being fed with tumor lysates. Optimal-length, naturally processed, and MHC class I– or class II–presented tumor peptides were comparatively poorly immunogenic in this model system.

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Immunosuppressive properties of CD95L-transduced “killer” hybrids created by fusing donor- and recipient-derived dendritic cells

Blood ◽

10.1182/blood.v98.12.3465 ◽

2001 ◽

Vol 98 (12) ◽

pp. 3465-3472 ◽

Cited By ~ 34

Author(s):

Hiroyuki Matsue ◽

Keiko Matsue ◽

Masahiro Kusuhara ◽

Tadashi Kumamoto ◽

Ko Okumura ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Organ Transplantation ◽

Mhc Class I ◽

Hematopoietic Cell Transplantation ◽

Class Ii ◽

Class I ◽

Delayed Type Hypersensitivity ◽

Mhc Molecules ◽

Dc Line

Abstract Allogeneic immune responses, which are initiated by dendritic cells (DCs) of both donor and host origins, remain a major obstacle in organ transplantation. Presentation of intact major histocompatibility complex (MHC) molecules by allogeneic DCs and allogeneic peptides by syngeneic DCs leads to complex allogeneic immune responses. This study reports a novel strategy designed to suppress both pathways. A stable DC line XS106 (A/J mouse origin) was transfected with CD95L cDNA and fused with splenic DCs purified from allogeneic BALB/c mice. The resulting “killer” DC-DC hybrids: (1) expressed CD95L and MHC class I and class II molecules of both A/J and BALB/c origins, while maintaining otherwise characteristic surface phenotypes of mature DCs; (2) inhibited MHC class I– and class II–restricted mixed leukocyte reactions between the parental strains by triggering apoptosis of alloreactive T cells; and (3) abolished delayed-type hypersensitivity responses of A/J (and BALB/c) mice to BALB/c-associated (and A/J-associated) alloantigens when injected intravenously into A/J (and BALB/c) mice. The onset of graft-versus-host disease in (BALB/c × A/J) F1 hosts receiving A/J-derived hematopoietic cell transplantation was suppressed significantly (P < .001) by killer DC-DC hybrid treatment. These results form both technical and conceptual frameworks for clinical applications of CD95L-transduced killer hybrids created between donor DCs and recipient DCs in the prevention of allogeneic immune responses following organ transplantation.

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Auranofin, an immunosuppressive drug, inhibits MHC class I and MHC class II pathways of antigen presentation in dendritic cells

Archives of Pharmacal Research ◽

10.1007/s12272-001-1166-9 ◽

2008 ◽

Vol 31 (3) ◽

pp. 370-376 ◽

Cited By ~ 7

Author(s):

Shinha Han ◽

Kwanghee Kim ◽

Youngcheon Song ◽

Hyunyul Kim ◽

Jeunghak Kwon ◽

...

Keyword(s):

Dendritic Cells ◽

Antigen Presentation ◽

Mhc Class I ◽

Mhc Class Ii ◽

Class Ii ◽

Immunosuppressive Drug ◽

Class I

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Induction of MHC Class I Presentation of Exogenous Antigen by Dendritic Cells Is Controlled by CD4+ T Cells Engaging Class II Molecules in Cholesterol-Rich Domains

The Journal of Immunology ◽

10.4049/jimmunol.168.3.1172 ◽

2002 ◽

Vol 168 (3) ◽

pp. 1172-1180 ◽

Cited By ~ 37

Author(s):

Patrick Machy ◽

Karine Serre ◽

Marjorie Baillet ◽

Lee Leserman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cd4 T Cells ◽

Class Ii ◽

Class I ◽

Exogenous Antigen

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Infection of mouse bone marrow-derived dendritic cells with recombinant adenovirus vectors leads to presentation of encoded antigen by both MHC class I and class II molecules—potential benefits in vaccine design

Vaccine ◽

10.1016/s0264-410x(02)00448-6 ◽

2002 ◽

Vol 21 (3-4) ◽

pp. 231-242 ◽

Cited By ~ 23

Author(s):

Osquel Barroso Herrera ◽

Sara Brett ◽

Robert I Lechler

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Mhc Class I ◽

Recombinant Adenovirus ◽

Vaccine Design ◽

Class Ii ◽

Class I ◽

Mouse Bone Marrow ◽

Potential Benefits ◽

Adenovirus Vectors

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Mature dendritic cells pulsed with freeze–thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4+ and CD8+ T lymphocyte responses

Blood ◽

10.1182/blood.v96.5.1857.h8001857_1857_1864 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1857-1864 ◽

Cited By ~ 1

Author(s):

Wolfgang Herr ◽

Elena Ranieri ◽

Walter Olson ◽

Hassane Zarour ◽

Loreto Gesualdo ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mhc Class I ◽

T Cell Responses ◽

Class Ii ◽

Interferon Γ ◽

Class I ◽

Freeze Thaw ◽

Cell Responses

Immunotherapy trials targeting the induction of tumor-reactive T-cell responses in cancer patients appear to hold significant promise. Because nonmutated lineage-specific antigens and mutated idiotypic antigens may be coexpressed by tumor cells, the use of autologous tumor material to promote the broadest range of antitumor T-cell specificities has significant clinical potential in cancer vaccination trials. As a model for vaccination in the cancer setting, we chose to analyze the promotion of T-cell responses against Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell line (B-LCL)–derived antigens in vitro. A series of bulk antigenic formats (freeze–thaw lysate, trifluoroacetic acid lysate, extracted membranes, affinity-purified MHC class I– and class II–presented peptides, acid-eluted peptides) prepared from EBV B-LCLs were tested for their ability to stimulate EBV B-LCL–reactive CD4+ and CD8+ T lymphocytes in vitro when pulsed onto autologous dendritic cells (DCs). DC presentation of freeze–thaw lysate material derived from (either autologous or allogeneic) EBV B-LCLs with an Mr of 10 kd or larger stimulated optimal anti-EBV B-LCL responsiveness from freshly isolated CD4+ and CD8+ peripheral blood T cells. These in vivo “memory” T-cell responses were observed only in EBV-seropositive donors. CD4+ T-cell responses to lysate-pulsed DCs were Th1 type (ie, strong interferon-γ and weak interleukin-5 responses). While CD8+ T-cell responses were also observed in interferon-γ Elispot assays and in cytotoxicity assays, these responses were of low frequency unless the DC stimulators were induced to “mature” after being fed with tumor lysates. Optimal-length, naturally processed, and MHC class I– or class II–presented tumor peptides were comparatively poorly immunogenic in this model system.

Download Full-text