Lymphocytes are the central recognition elements of the immune response. They are divided into 2 major classes - T and B cells - and each of these are further subdivided into functional and phenotypic subclasses. A major goal of this grant is to define the full maturation sequence of both T and B cell lineages, from effector cells back to a hematopoietic stem cells. New methods of clonging pre-B and pre-T cells will be combined with 3-color FACS sorting and clonal functional analyses to define stages and microenvironments wherein these cells commit to antigen receptor expression, homing receptor expression, function, phenotype, self-nonself discrimination, and MHC restricted recognition of antigens. At each stage of differentiation the regulation of expression of cloned T and B cell specific genes shall also be examined, including the rearrangement, transcription, and class-switching of immunoglobulin and T cell receptor genes. A second major goal is to identify the homing patterns of defined subsets of lymphocytes. Two have been defined (for lymph node high endothelial venules (HEV) and Peyer's patch HEV) by function and specific anti-receptor monoclonal antibodies. The lymph node receptor is a branched-chain polypeptide whose amino acid sequence we know. In this grant three other biological homing properties will be studied -BAlpha immunoblasts to gut lamina propria, TC and TD homing to target antigen sites, and pre-T cells to the thymus. An eventual aim is to identify a family of homing receptors, clone their genes, and test their function. A second major aim is to define the role of homing receptors in metastasis of lymphoid tumors. Two aspects of oncogenesis shall be studied: The Receptor Mediated Leukemogenesis Hypothesis will be tested directly to determine if leukemogenic retroviruses bind to antigen receptors on T and B cells a) to infect and transform them, and b) to stimulate their entry into the mitotic cycle. The second aspect of oncogenesis studied will be the role of 6C3Ag - B-lineage transformation specific molecule on all mouse pre-B/early B cell lymphomas - in normal and neoplastic B cell maturation. 6C3Ag is present also on cloned bone marrow stromal elements which support the growth and maturation of pre-B cells. In this grant we shall test the hypothesis that 6C3Ag is a cell surface growth and/or differentiation factor for early pre-B lineage cells, and that neoplastic development is the inappropriate expression of this gene in cells bearing receptors for its products (Receptor Mediated Leukemogenesis). Finally, to study the evolutionary antecedents to the co-evolving MHC and T cells which recognize it, this grant will also identify in the highest invertebrates - the Protochordates - the polymorphic genes and products involved in natural allorecognition in the wild, and whether these are encoded by genes hybridizing to vertebrate MHC and Thy-1 genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA042551-05
Application #
3479386
Study Section
Special Emphasis Panel (SRC)
Project Start
1986-08-01
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Cheshier, Samuel H; Prohaska, Susan S; Weissman, Irving L (2007) The effect of bleeding on hematopoietic stem cell cycling and self-renewal. Stem Cells Dev 16:707-17
Allsopp, Richard C; Morin, Gregg B; DePinho, Ronald et al. (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102:517-20
Allsopp, Richard C; Morin, Gregg B; Horner, James W et al. (2003) Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat Med 9:369-71
Chadwick-Furman, Nanette E; Weissman, Irving L (2003) Effects of allogeneic contact on life-history traits of the colonial ascidian Botryllus schlosseri in Monterey Bay. Biol Bull 205:133-43
Jaiswal, Siddhartha; Traver, David; Miyamoto, Toshihiro et al. (2003) Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci U S A 100:10002-7
Nakorn, Thanyaphong Na; Miyamoto, Toshihiro; Weissman, Irving L (2003) Characterization of mouse clonogenic megakaryocyte progenitors. Proc Natl Acad Sci U S A 100:205-10
Domen, Jos; Weissman, Irving L (2003) Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeutic agents in vivo when overexpressing bcl-2. Exp Hematol 31:631-9
King, Angela G; Kondo, Motonari; Scherer, David C et al. (2002) Lineage infidelity in myeloid cells with TCR gene rearrangement: a latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling. Proc Natl Acad Sci U S A 99:4508-13
Allsopp, Richard C; Cheshier, Samuel; Weissman, Irving L (2002) Telomerase activation and rejuvenation of telomere length in stimulated T cells derived from serially transplanted hematopoietic stem cells. J Exp Med 196:1427-33
Na Nakorn, Thanyaphong; Traver, David; Weissman, Irving L et al. (2002) Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S. J Clin Invest 109:1579-85

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