Large granular lymphocyte (LGL) leukemia is a chronic T cell lymphoproliferation associated with immune-mediated cytopenias and expansion of clonal cytotoxic T cells (CTL). LGL CTL defies natural regulation, and their proliferation appears to be maintained by extrinsic triggers. Additionally, the clonal CTL appear to be the effectors that mediate an immune attack presumably directed against hematopoietic progenitors. As an experimental model LGL leukemia offers an advantage of availability of clonal effector cells and the target cells they recognize. The pathophysiology of LGL leukemia may correspond to a polarized clonal response that constitutes a suitable model for characterizing the role of individual pathogenic T cell clones but also as a basis for comparison with the polyclonal T cell responses accompanying other causes of immune-mediated bone marrow failure states. Under normal circumstances, in the process of immune reaction to specific antigens, immunodominant T cell clones expand. The unique antigen-specific portion of the T cell receptor (TCR), the complementary determining region-3 (CDR3) of the variable portion of the a-chain (VB), can serve as a molecular signature (clonotype) for the antigen-specific T cell clones. Hypothesis: The specificity of the antigenic recognition in LGL may determine its hematologic presentation and cryptic CTL-mediated expansions, analogous to LGL leukemia, may be responsible also in other forms of immune cytopenias. CDR3 clonotypes may constitute suitable targets to study clonal processes and development of new diagnostic tools.
Specific Aims : 1) Characterization of LGL T cell clonotypes will allow us to determine if similar clonotypes are shared between the patients (or possibly also found in healthy individuals), as well as to design a new class of diagnostic tools based on the quantitation of pathogenic clones using clonotypic PCR. 2) The specificity of antigenic recognition in LGL leukemia may determine the types of clinical presentation (e.g. anemia, neutropenia). Inhibitory and cytotoxic activity of clonal LGL will be tested against autologous and allogeneic erythroid and myeloid precursors, as well as cell lines and undifferentiated CD34+ cells. 3) Isolation of LGL clones will allow for the generation of soluble TCR molecules that will be applied to identify cellular target cells for LGL CTL. 4) Identification of LGL specific clonotypes will be applied to measure the anti-idiotypic responses directed against LGL and control clones in patients to determine the role of anti-idiotypic feedback in the regulation of autonomous and physiologic clonal expansions. The long-term goals of our proposal include establishment of novel diagnostic strategy based on molecular analysis of TCR. Our studies concentrate on LGL leukemia but in general, molecular analysis of the T cell repertoire can be applied to the study of many hematologic conditions, including immune surveillance of leukemia evolution, immune-mediated bone marrow failure and graft versus host disease.
|Sanikommu, Srinivasa R; Clemente, Michael J; Chomczynski, Peter et al. (2018) Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). Leuk Lymphoma 59:416-422|
|Jobe, F; Patel, B; Kuzmanovic, T et al. (2017) Deletion of Ptpn1 induces myeloproliferative neoplasm. Leukemia 31:1229-1234|
|Clemente, Michael J; Przychodzen, Bartlomiej; Jerez, Andres et al. (2013) Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes. Blood 122:4077-85|
|Clemente, Michael J; Wlodarski, Marcin W; Makishima, Hideki et al. (2011) Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia. Blood 118:4384-93|
|Mohan, Sanjay R; Clemente, Michael J; Afable, Manuel et al. (2009) Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia. Haematologica 94:1407-14|
|Babel, Nina; Brestrich, Gordon; Gondek, Lukasz P et al. (2009) Clonotype analysis of cytomegalovirus-specific cytotoxic T lymphocytes. J Am Soc Nephrol 20:344-52|
|McIver, Z; Serio, B; Dunbar, A et al. (2008) Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation. Br J Haematol 141:170-8|
|Schade, Andrew E; Schieven, Gary L; Townsend, Robert et al. (2008) Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 111:1366-77|
|Wlodarski, Marcin Wojciech; Nearman, Zachary; Jiang, Ying et al. (2008) Clonal predominance of CD8(+) T cells in patients with unexplained neutropenia. Exp Hematol 36:293-300|
|Nearman, Zachary P; Wlodarski, Marcin; Jankowska, Anna M et al. (2007) Immunogenetic factors determining the evolution of T-cell large granular lymphocyte leukaemia and associated cytopenias. Br J Haematol 136:237-48|
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