scholarly journals A Modified Tyrosinase-Related Protein 2 Epitope Generates High-Affinity Tumor-Specific T Cells but Does Not Mediate Therapeutic Efficacy in an Intradermal Tumor Model

2006 ◽  
Vol 177 (1) ◽  
pp. 155-161 ◽  
Author(s):  
Jennifer A. McWilliams ◽  
Sean M. McGurran ◽  
Steven W. Dow ◽  
Jill E. Slansky ◽  
Ross M. Kedl
Keyword(s):  
T Cells ◽  
Therapeutic Efficacy ◽  
Tumor Model ◽  
Related Protein ◽  
High Affinity ◽  
Tyrosinase Related Protein

scholarly journals Evidence of the extrathymic development of tyrosinase-related protein-2-recognizing CD8+ T cells with low avidity

Immunology ◽  
2001 ◽  
Vol 104 (1) ◽  
pp. 67-74 ◽  
Author(s):  
Mamoru Harada, ◽  
Hisakata Yamada ◽  
Katsunori Tatsugami ◽  
Kikuo Nomoto
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Related Protein ◽  
Tyrosinase Related Protein

scholarly journals Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis

Angiogenesis ◽  
2017 ◽  
Vol 20 (4) ◽  
pp. 615-628 ◽  
Author(s):  
Yuri K. Peterson ◽  
Patrick Nasarre ◽  
Ingrid V. Bonilla ◽  
Eleanor Hilliard ◽  
Jennifer Samples ◽  
...  
Keyword(s):  
T Cells ◽  
Nuclear Factor ◽  
Related Protein ◽  
Activated T Cells ◽  
High Affinity ◽  
High Affinity Receptor ◽  
Affinity Receptor

scholarly journals Coupling and Uncoupling of Tumor Immunity and Autoimmunity

1999 ◽  
Vol 190 (11) ◽  
pp. 1717-1722 ◽  
Author(s):  
Wilbur B. Bowne ◽  
Roopa Srinivasan ◽  
Jedd D. Wolchok ◽  
William G. Hawkins ◽  
Nathalie E. Blachere ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Cytotoxic T Cells ◽  
Active Immunization ◽  
Dna Immunization ◽  
Related Protein ◽  
Cd4 Cells ◽  
Differentiation Antigen ◽  
System Tumor ◽  
Tyrosinase Related Protein

Self-antigens, in the form of differentiation antigens, are commonly recognized by the immune system on melanoma and other cancers. We have shown previously that active immunization of mice against the melanocyte differentiation antigen, a tyrosinase-related protein (TRP) gp75TRP-1 (the brown locus protein) expressed by melanomas, could induce tumor immunity and autoimmunity manifested as depigmentation. In this system, tumor immunity and autoimmunity were mediated by autoantibodies. Here, we characterize immunity against another tyrosinase family glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and method of immunization. As observed previously for gp75TRP-1, immunity was induced by DNA immunization against a xenogeneic form of TRP-2, but not against the syngeneic gene, and depended on CD4+ cells. Immunization against TRP-2 induced autoantibodies and autoreactive cytotoxic T cells. In contrast to immunization against gp75TRP-1, both tumor immunity and autoimmunity required CD8+ T cells, but not antibodies. Only autoimmunity required perforin, whereas tumor immunity proceeded in the absence of perforin. Thus, immunity induced against two closely related autoantigens that are highly conserved throughout vertebrate evolution involved qualitatively different mechanisms, i.e., antibody versus CD8+ T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity.

scholarly journals Non-deletional CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

2020 ◽  
Author(s):  
Emily Nestor Truckenbrod ◽  
Kristina S Burrack ◽  
Todd P Knutson ◽  
Henrique Borges da Silva ◽  
Katharine E Block ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Related Protein ◽  
Wild Type ◽  
Clonal Deletion ◽  
Cd25 Expression ◽  
Self Tolerance ◽  
Tyrosinase Related Protein

AbstractSelf-specific CD8+ T cells often escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice that express or lack this enzyme due to deficiency in Dct, which encodes Trp2. The size, phenotype, and gene expression profile of the pre-immune Trp2/Kb-specific pool were similar in wild-type (WT) and Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion, and scRNAseq revealed WT cells less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.

scholarly journals CD8+ T cell self-tolerance permits responsiveness but limits tissue damage

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Emily N Truckenbrod ◽  
Kristina S Burrack ◽  
Todd P Knutson ◽  
Henrique Borges da Silva ◽  
Katharine E Block ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Protein ◽  
Wild Type ◽  
Clonal Deletion ◽  
Self Tolerance ◽  
Tyrosinase Related Protein

Self-specific CD8+ T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8+ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Hence, CD8+ T cell self-specificity is poorly predicted by precursor frequency, phenotype or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.

scholarly journals Adult and Cord Blood-Derived High-Affinity gB-CAR-T Cells Effectively React Against Human Cytomegalovirus Infections

2020 ◽  
Vol 31 (7-8) ◽  
pp. 423-439 ◽  
Author(s):  
Henning Olbrich ◽  
Sebastian J. Theobald ◽  
Constanze Slabik ◽  
Laura Gerasch ◽  
Andreas Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Human Cytomegalovirus ◽  
High Affinity ◽  
Car T Cells ◽  
Car T ◽  
Cytomegalovirus Infections

112 Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A124-A124
Author(s):  
Letizia Giardino ◽  
Ryan Gilbreth ◽  
Cui Chen ◽  
Erin Sult ◽  
Noel Monks ◽  
...  
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Single Chain ◽  
High Affinity ◽  
Car T Cells ◽  
Car T ◽  
Animal Care ◽  
Cytotoxic Function

BackgroundChimeric antigen receptor (CAR)-T therapy has yielded impressive clinical results in hematological malignancies and it is a promising approach for solid tumor treatment. However, toxicity, including on-target off-tumor antigen binding, is a concern hampering its broader use.MethodsIn selecting a lead CAR-T candidate against the oncofetal antigen glypican 3 (GPC3), we compared CAR bearing a low and high affinity single-chain variable fragment (scFv,) binding to the same epitope and cross-reactive with murine GPC3. We characterized low and high affinity CAR-T cells immunophenotype and effector function in vitro, followed by in vivo efficacy and safety studies in hepatocellular carcinoma (HCC) xenograft models.ResultsCompared to the high-affinity construct, the low-affinity CAR maintained cytotoxic function but did not show in vivo toxicity. High-affinity CAR-induced toxicity was caused by on-target off-tumor binding, based on the evidence that high-affinity but not low-affinity CAR, were toxic in non-tumor bearing mice and accumulated in organs with low expression of GPC3. To add another layer of safety, we developed a mean to target and eliminate CAR-T cells using anti-TNFα antibody therapy post-CAR-T infusion. This antibody functioned by eliminating early antigen-activated CAR-T cells, but not all CAR-T cells, allowing a margin where the toxic response could be effectively decoupled from anti-tumor efficacy.ConclusionsSelecting a domain with higher off-rate improved the quality of the CAR-T cells by maintaining cytotoxic function while reducing cytokine production and activation upon antigen engagement. By exploring additional traits of the CAR-T cells post-activation, we further identified a mechanism whereby we could use approved therapeutics and apply them as an exogenous kill switch that would eliminate early activated CAR-T following antigen engagement in vivo. By combining the reduced affinity CAR with this exogenous control mechanism, we provide evidence that we can modulate and control CAR-mediated toxicity.Ethics ApprovalAll animal experiments were conducted in a facility accredited by the Association for Assessment of Laboratory Animal Care (AALAC) under Institutional Animal Care and Use Committee (IACUC) guidelines and appropriate animal research approval.

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