Title | T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Blachere NE, Orange DE, Santomasso BD, Doerner J, Foo PK, Herre M, Fak J, Monette S, Gantman EC, Frank MO, Darnell RB |
Journal | Eur J Immunol |
Volume | 44 |
Issue | 11 |
Pagination | 3240-51 |
Date Published | 2014 Nov |
ISSN | 1521-4141 |
Keywords | Adoptive Transfer, Animals, Antibodies, Monoclonal, Murine-Derived, Antigens, Neoplasm, Antineoplastic Agents, Autoimmunity, B-Lymphocytes, beta-Galactosidase, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Central Nervous System, Immune Tolerance, Immunization, Immunologic Factors, Immunologic Memory, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Paraneoplastic Syndromes, Nervous System, Rituximab, RNA-Binding Proteins |
Abstract | Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. |
DOI | 10.1002/eji.201444624 |
Alternate Journal | Eur. J. Immunol. |
PubMed ID | 25103845 |
PubMed Central ID | PMC4296561 |
Grant List | R01 NS081706 / NS / NINDS NIH HHS / United States KL2 TR000151 / TR / NCATS NIH HHS / United States UL1 TR000043 / TR / NCATS NIH HHS / United States R01 NS034389 / NS / NINDS NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States 8 KL2 TR000151 / TR / NCATS NIH HHS / United States UL1 RR024143 / RR / NCRR NIH HHS / United States / / Howard Hughes Medical Institute / United States |
Submitted by api_import on December 20, 2019 - 1:39pm