Major histocompatibility complex class II-mediated inhibition of hematopoiesis in long-term marrow cultures involves apoptosis and is prevented by c-kit ligand.

Expression of major histocompatibility complex (MHC) class II molecules is developmentally regulated and lineage dependent. Their role in hematopoiesis is not well defined. Previous studies in a canine model showed that dogs given 920 cGy of total body irradiation, transplanted with autologous marrow, and treated with anti-MHC class II monoclonal antibody (MoAb) immediately posttransplant experienced only a transient granulocyte recovery that was followed by graft failure. In the present study, the effect of anti-MHC class II MoAbs on canine in vitro hematopoiesis was investigated. Anti-MHC class II MoAb H81.9 or B1F6 (both recognizing nonpolymorphic determinants) had no inhibitory effect when added directly to colony-forming unit-granulocyte-macrophage (CFU-GM) grown in agar. However, the addition of intact MoAb or as F(ab')2 fragments to long-term marrow cultures (LTMCs) resulted in a dose-dependent inhibition of the generation of CFU-GM among nonadherent cells. Inhibition was most profound with MoAb added at the time of initiation of culture. However, even if MoAb was added 3 weeks after recharging LTMCs, CFU-GM generation rapidly decreased. In addition, the number of adherent cells in LTMCs decreased; predominantly fibroblast-like cells with prominent cytoplasmic vesiculation remained. Acridine orange/ethidium bromide staining and TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) tests showed an increase in the proportion of apoptotic cells in both the nonadherent and adherent compartments. Binding of anti-MHC class II MoAb to unfractionated marrow cells resulted in an increase in free (Ca2+)i; no changes in tyrosine phosphorylation pattern were observed. The addition of stem cell factor (SCF), but not granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, to LTMCs prevented apoptosis, and the generation of CFU-GM was indistinguishable from controls. Similarly, a supportive adherent layer was maintained. Thus, anti-MHC class II MoAbs interfere with hematopoiesis both in vitro and in vivo. The mechanism involves programmed cell death in subpopulations of adherent and nonadherent cells. Inhibition of hematopoiesis is abrogated by exogenous SCF.

[1]  H. Deeg,et al.  Differentiation of canine bone marrow cells with hemopoietic characteristics from an adherent stromal cell precursor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[2]  H. Deeg,et al.  MHC antigens and haemopoiesis. , 1994, Transplant immunology.

[3]  C. Verfaillie,et al.  CD34+/CD33- cells reselected from macrophage inflammatory protein 1 alpha+interleukin-3--supplemented "stroma-noncontact" cultures are highly enriched for long-term bone marrow culture initiating cells. , 1994, Blood.

[4]  H. Deeg,et al.  Rescue from anti-MHC class II antibody-mediated marrow graft failure by c-kit ligand. , 1994, Blood.

[5]  L. Terstappen,et al.  Lymphoid and myeloid differentiation of single human CD34+, HLA-DR+, CD38- hematopoietic stem cells. , 1994, Blood.

[6]  R. Hoffman,et al.  Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells. , 1994, Experimental hematology.

[7]  G. Ossenkoppele,et al.  Apoptosis in tumor necrosis factor-alpha-dependent, monocyte-mediated leukemic cell death: a functional, morphologic, and flow-cytometric analysis. , 1993, Experimental hematology.

[8]  J. Freed,et al.  Ligation of major histocompatibility complex class II molecules mediates apoptotic cell death in resting B lymphocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Deeg,et al.  Major histocompatibility complex class II molecules, hemopoiesis and the marrow microenvironment. , 1993, Bone marrow transplantation.

[10]  D. Metcalfe,et al.  IL-3-dependent murine mast cells undergo apoptosis on removal of IL-3. Prevention of apoptosis by c-kit ligand. , 1993, Journal of immunology.

[11]  P. Linsley,et al.  Costimulation with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 augments activation-induced death of antigen-specific CD4+ T lymphocytes. , 1993, Journal of immunology.

[12]  K. Muta,et al.  Apoptosis of human erythroid colony‐forming cells is decreased by stem cell factor and insulin‐like growth factor I as well as erythropoietin , 1993, Journal of cellular physiology.

[13]  J. Ledbetter,et al.  Activation with superantigens induces programmed death in antigen‐primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18‐dependent mechanism , 1993, European journal of immunology.

[14]  G. Schieven,et al.  Ultraviolet radiation rapidly induces tyrosine phosphorylation and calcium signaling in lymphocytes. , 1993, Molecular biology of the cell.

[15]  H. Deeg,et al.  Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation. , 1993, Blood.

[16]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[17]  R. Storb,et al.  Specific growth inhibition of primitive hematopoietic progenitor cells mediated through monoclonal antibody binding to major histocompatibility class II molecules. , 1992, Blood.

[18]  R. Hoffman,et al.  Human hematopoietic stem cell adherence to cytokines and matrix molecules. , 1992, The Journal of clinical investigation.

[19]  S. Kanner,et al.  CD2/LFA-3 ligation induces phospholipase-C gamma 1 tyrosine phosphorylation and regulates CD3 signaling. , 1992, Journal of immunology.

[20]  L. Glimcher,et al.  Sequences and factors: a guide to MHC class-II transcription. , 1992, Annual review of immunology.

[21]  T. Tedder,et al.  Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway. , 1991, Journal of immunology.

[22]  I. Weissman,et al.  Lymphoid reconstitution of the human fetal thymus in SCID mice with CD34+ precursor cells , 1991, The Journal of experimental medicine.

[23]  H. Deeg,et al.  Late failure of autologous marrow grafts in lethally irradiated dogs given anti-class II monoclonal antibody. , 1991, Blood.

[24]  G. Schieven,et al.  Signal transduction by HLA-DR is mediated by tyrosine kinase(s) and regulated by CD45 in activated T cells. , 1991, Human immunology.

[25]  J. Ledbetter,et al.  Homotypic aggregation of human cell lines by HLA class II‐, class Ia‐ and HLA‐G‐specific monoclonal antibodies , 1991, European journal of immunology.

[26]  H. Deeg,et al.  UV irradiation of lymphocytes triggers an increase in intracellular Ca2+ and prevents lectin-stimulated Ca2+ mobilization: evidence for UV- and nifedipine-sensitive Ca2+ channels. , 1991, Experimental hematology.

[27]  R. Storb,et al.  Molecular cloning and in vivo evaluation of canine granulocyte-macrophage colony-stimulating factor. , 1991, Blood.

[28]  R. Hoffman,et al.  Human CD34+ HLA-DR- bone marrow cells contain progenitor cells capable of self-renewal, multilineage differentiation, and long-term in vitro hematopoiesis. , 1991, Blood cells.

[29]  J. Thorner,et al.  Novel yeast protein kinase (YPK1 gene product) is a 40-kilodalton phosphotyrosyl protein associated with protein-tyrosine kinase activity , 1990, Molecular and cellular biology.

[30]  J. Madrenas,et al.  Regulation of MHC transcription. , 1990, Transplantation.

[31]  R. Geha,et al.  Engagement of major histocompatibility complex class II molecules induces sustained, lymphocyte function-associated molecule 1-dependent cell adhesion , 1990, The Journal of experimental medicine.

[32]  C. Verfaillie,et al.  Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma , 1990, The Journal of experimental medicine.

[33]  J. Ellwart,et al.  HLA-class II antigens on hemopoietic and stromal cells in human micro long-term bone marrow cultures. , 1990, Experimental hematology.

[34]  T. Dexter,et al.  Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis , 1990, Nature.

[35]  K. Dorshkind,et al.  Regulation of hemopoiesis by bone marrow stromal cells and their products. , 1990, Annual review of immunology.

[36]  R. Storb,et al.  Long-term culture of canine bone marrow cells. , 1989, Experimental hematology.

[37]  H. Deeg,et al.  SELECTIVE INHIBITION OF THE CANINE MIXED LYMPHOCYTE RESPONSE BY HLA‐DR AND DP‐REACTIVE MONOCLONAL ANTIBODIES , 1988, Transplantation.

[38]  B. Torok-Storb.  Hematopoietic cellular interactions: role of the major histocompatibility complex (MHC). , 1988, Blood cells.

[39]  J. Guardiola,et al.  Distinct mechanisms regulate MHC class II gene expression in B cells and macrophages. , 1987, Journal of immunology.

[40]  J. Nemunaitis,et al.  Simian virus 40-transformed adherent cells from human long-term marrow cultures: cloned cell lines produce cells with stromal and hematopoietic characteristics. , 1987, Blood.

[41]  H. Deeg,et al.  Canine pluripotent hematopoietic stem cells and CFU-GM express Ia-like antigens as recognized by two different class II-specific monoclonal antibodies. , 1987, Blood.

[42]  P. Rabinovitch,et al.  Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. , 1986, Journal of immunology.

[43]  M. Wicha,et al.  Extracellular matrix promotes the growth and differentiation of murine hematopoietic cells in vitro. , 1985, The Journal of clinical investigation.

[44]  H. Deeg,et al.  Failure of autologous marrow reconstitution after cytolytic treatment of marrow with anti-Ia monoclonal antibody. , 1985, Blood.

[45]  J. Singer,et al.  The generation of human long-term marrow cultures from marrow depleted of Ia (HLA-DR) positive cells. , 1984, Blood.

[46]  R. Alejandro,et al.  Monoclonal antibodies recognizing canine and human Ia-like antigens. , 1984, Transplantation.

[47]  L. Nadler,et al.  Discordant expression of human Ia-like antigens on hematopoietic progenitor cells. , 1984, Journal of immunology.

[48]  E. Shevach,et al.  Non-activated guinea-pig T cells and thymocytes express Ia antigens: FACS analysis with alloantibodies and monoclonal antibodies. , 1984, Immunology.

[49]  J. Hansen,et al.  HLA-DR antigens on lymphoid cells differ from those on myeloid cells , 1983, Nature.

[50]  D. Birnbaum,et al.  The importance of cross-reactions between species: mouse allo-anti-Ia monoclonal antibodies as a powerful tool to define human Ia subsets. , 1983, Human immunology.

[51]  P. Parham,et al.  Monoclonal antibodies: purification, fragmentation and application to structural and functional studies of class I MHC antigens. , 1982, Journal of immunological methods.

[52]  A. Wyllie.  Cell death: a new classification separating apoptosis from necrosis , 1981 .

[53]  P. Edwards,et al.  Expression of cell-surface HLA-DR, HLA-ABC and glycophorin during erythroid differentiation , 1981, Nature.

[54]  R. Winchester,et al.  Continuous human bone marrow culture: Ia antigen characterization of probable pluripotential stem cells. , 1980, Blood.

[55]  D. Götze.  The Major Histocompatibility System in Man and Animals , 2012, Springer Berlin Heidelberg.

[56]  L. Lajtha,et al.  Conditions controlling the proliferation of haemopoietic stem cells in vitro , 1977, Journal of cellular physiology.