Reconstitution of Early Lymphoid Proliferation and Immune Function in Jak3-Deficient Mice by Interleukin-3

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1906-1914 ◽  
Author(s):  
Michael P. Brown ◽  
Tetsuya Nosaka ◽  
Ralph A. Tripp ◽  
James Brooks ◽  
Jan M.A. van Deursen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cytotoxic T Lymphocyte ◽  
Severe Combined Immunodeficiency ◽  
Fold Increase ◽  
Receptor Activation ◽  
Beneficial Effects ◽  
Interleukin 7 ◽  
Histocompatibility Complex ◽  
Lymphoid Progenitors

Abstract Expansion of early lymphoid progenitors requires interleukin-7 (IL-7), which functions through γc-mediated receptor activation of Jak3. Jak3 deficiency is a cause of severe combined immunodeficiency (SCID) in humans and mice. IL-3 activates many of the same signaling pathways as IL-7, such as Stat5, but achieves this effect through the activation of Jak2 rather than Jak3. We hypothesized that expansion of an IL-7–responsive precursor population through a Jak3-independent pathway using IL-3 may stimulate early lymphoid progenitors and restore lymphopoiesis in Jak3−/− mice. Newborn Jak3−/− mice that were injected with IL-3 demonstrated thymic enlargement, a 2- to 20-fold increase in thymocyte numbers, and up to a 10-fold expansion in the number of CD4+, CD8+, and B220+/IgM+ splenic lymphocytes, consistent with an effect upon an early lymphoid progenitor population. In contrast to control mice, IL-3–treated Jak3−/− mice challenged with the allogeneic major histocompatibility complex (MHC) class I-bearing tumor P815 developed a specific CD8-dependent cytotoxic T lymphocyte (CTL) response. IL-3–treated mice also mounted influenza-specific CTL responses and survival was prolonged. The beneficial effects of IL-3 are proposed to be produced by stimulation of a lymphoid precursor population of IL-7R+/IL-3R+ cells that we identified in wild-type bone marrow. In vitro, we show that an early IL-7R+ lymphoid progenitor population expresses IL-3R and proliferates in response to IL-3 and that IL-3 activates Stat5 comparably to IL-7. Clinically, IL-3 may therefore be useful treatment for X-linked and Jak3-deficient SCID patients who lack bone marrow donors.

Reconstitution of Early Lymphoid Proliferation and Immune Function in Jak3-Deficient Mice by Interleukin-3

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1906-1914
Author(s):  
Michael P. Brown ◽  
Tetsuya Nosaka ◽  
Ralph A. Tripp ◽  
James Brooks ◽  
Jan M.A. van Deursen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cytotoxic T Lymphocyte ◽  
Severe Combined Immunodeficiency ◽  
Fold Increase ◽  
Receptor Activation ◽  
Beneficial Effects ◽  
Interleukin 7 ◽  
Histocompatibility Complex ◽  
Lymphoid Progenitors

Expansion of early lymphoid progenitors requires interleukin-7 (IL-7), which functions through γc-mediated receptor activation of Jak3. Jak3 deficiency is a cause of severe combined immunodeficiency (SCID) in humans and mice. IL-3 activates many of the same signaling pathways as IL-7, such as Stat5, but achieves this effect through the activation of Jak2 rather than Jak3. We hypothesized that expansion of an IL-7–responsive precursor population through a Jak3-independent pathway using IL-3 may stimulate early lymphoid progenitors and restore lymphopoiesis in Jak3−/− mice. Newborn Jak3−/− mice that were injected with IL-3 demonstrated thymic enlargement, a 2- to 20-fold increase in thymocyte numbers, and up to a 10-fold expansion in the number of CD4+, CD8+, and B220+/IgM+ splenic lymphocytes, consistent with an effect upon an early lymphoid progenitor population. In contrast to control mice, IL-3–treated Jak3−/− mice challenged with the allogeneic major histocompatibility complex (MHC) class I-bearing tumor P815 developed a specific CD8-dependent cytotoxic T lymphocyte (CTL) response. IL-3–treated mice also mounted influenza-specific CTL responses and survival was prolonged. The beneficial effects of IL-3 are proposed to be produced by stimulation of a lymphoid precursor population of IL-7R+/IL-3R+ cells that we identified in wild-type bone marrow. In vitro, we show that an early IL-7R+ lymphoid progenitor population expresses IL-3R and proliferates in response to IL-3 and that IL-3 activates Stat5 comparably to IL-7. Clinically, IL-3 may therefore be useful treatment for X-linked and Jak3-deficient SCID patients who lack bone marrow donors.

scholarly journals Frequency analysis of cytotoxic T lymphocyte precursors in chimeric mice. Evidence for intrathymic maturation of clonally distinct self-major histocompatibility complex- and allo-major histocompatiblilty complex-restricted virus-specific T cells.

1981 ◽  
Vol 153 (6) ◽  
pp. 1517-1532 ◽  
Author(s):  
H Wagner ◽  
C Hardt ◽  
R Bartlett ◽  
H Stockinger ◽  
M Röllinghoff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Lymphocyte ◽  
Sendai Virus ◽  
Cytotoxic T Lymphocyte ◽  
Major Histocompatibility ◽  
Chimeric Mice ◽  
Histocompatibility Complex

To study whether the thymic major histocompatibility complex (MHC) imposes a constraint on the receptor repertoire of maturating cytotoxic T lymphocyte (CTL) precursors, the restriction phenotypes of virus-specific CTL of MHC-compatible and of MHC-incompatible thymus- and bone marrow-grafted (A X B)F1 chimeric mice were compared. Dependent on the mode of in vitro sensitization, thymocytes or splenocytes of both types of chimeric mice generated Sendai virus-specific, self-MHC-or allo-MHC-restricted CTL. By applying the limiting-dilution technique, the CTL-precursor (CTL-P) frequencies of self-MHC-restricted and allo-MHC-restricted virus-specific T cells as well as of alloreactive T cells were determined. The data obtained revealed that independent of MHC differences between thymus and bone marrow, the frequencies of self-MHC-restricted and allo-MHC-restricted CTL-P were comparable, and in the same older of magnitude as those previously determined in conventionally reared mice. Self-MHC-restricted, virus-specific CTL-P were in a three- to fivefold excess over allo-MHC-restricted CTL-P. A segregation analysis revealed that clonally distinct CTL-P give rise to either self-restricted or allo-MHC-restricted, virus-specific CTL. Both sets were found not only in the spleen, but also in the thymus of chimeric mice, formally demonstrating the intrathymic differentiation pathway of self-MHC as well of allo-MHC-restricted CTL-P. These data reveal no major constraint of the thymic MHC on the capacity of T cells to recognize viral antigens either in the context of self-MHC or of allogeneic MHC products.

Abstract 228: Short-term Cyclosporine Therapy Increases Ischemia-induced Endothelial Progenitor Cell Mobilization Through Manipulation Of The CD26 System

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Chao Hung Wang ◽  
Wen-Jin Cherng ◽  
I-Chang Hsieh ◽  
Ning-I Yang ◽  
Chi-Hsiao Yeh
Keyword(s):  
Bone Marrow ◽  
Critical Role ◽  
Fold Increase ◽  
Serum Levels ◽  
Short Term ◽  
Endothelial Progenitor ◽  
Beneficial Effects ◽  
Dpp Iv

Cyclosporine A (CsA), an immunosuppressant, has remarkably improved the short-term success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57 BL/6 mice were divided into control and CsA-treated groups. Circulating EPCs were enumerated before and after hindlimb ischemia was induced. Levels of stroma-derived factor-1α (SDF-1α), stem cell factor (SCF), vascular endothelial grow factor (VEGF), and granulocyte-colony stimulating factor (G-CSF) were measured in the blood. Compared to the controls, CsA treatment significantly increased the serum levels of SDF-1α and SCF (p < 0.001), but not of VEGF or G-CSF after ischemic stress. The CsA group displayed a significant increase in the number of circulating EPCs (with a 7-fold increase in sca-1 + KDR + cells and a 1.5-fold increase in c-kit + CD31 + cells versus the controls at 18 h after ischemia was induced, both p < 0.05). In vivo , CsA also caused 2- and 5-fold increases in the numbers of bone marrow-derived EPCs incorporated into the Matrigel and ischemic limbs, respectively (p < 0.05). In the peripheral blood, CsA significantly decreased CD26 + cell numbers (p < 0.001) and attenuated the plasma CD26/DPP IV activity (p < 0.001). CsA did not alter the acitivty of MMP-2 or MMP-9 in vitro or in vivo . Compared to the controls, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In conclusions, this study demonstrated that CsA manipulates the mobilization of bone marrow-derived EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogensis of ischemic tissues.

Abstract 1444: Overexpression Of Endothelial Nitric Oxide Synthase Restores Post-natal Neovascularization In Atherosclerosis.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Barend Mees ◽  
Ludovic Waeckel ◽  
Dong You ◽  
Dennie Tempel ◽  
Maria Godinho ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hind Limb ◽  
Fold Increase ◽  
Tissue Perfusion ◽  
Vessel Density ◽  
Plaque Size ◽  
Angiogenic Potential ◽  
Apoe Ko Mice ◽  
Apoe Ko

Alteration in post-ischemic neovascularization is a common complication of atherosclerotic disease. This results, at least in part, from abrogation of bone-marrow mononuclear cells (BM-MNC) pro-angiogenic potential. Overexpression of eNOS has been shown to promote vessel growth in the setting of ischemia. We hypothesized that eNOS overexpression could restore impaired neovascularization in atherosclerotic (ApoE KO) mice. Hind limb ischemia was induced in mice by right femoral artery ligation. After two weeks we evaluated tissue perfusion of the foot by Laser Doppler, vessel density in the hind limb by micro-angiography and histology, and atherosclerotic plaque size. In vitro BM-MNC cell culture assays were performed. Tissue perfusion and vessel density were 1.5-fold increased in transgenic mice overexpressing eNOS (eNOStg) as compared to wild type (WT) (P<0.001, n=10). Transplantation of 1x106 WT- or eNOStg BM-MNC in WT recipients caused a 1.5-fold increase in tissue perfusion and vessel density compared to injection of PBS (P<0.001, n=10). Next, we used ApoE KO mice and crossbreeds of eNOStg and ApoE KO mice (eNOStg*ApoE KO). Tissue perfusion and vessel density were 1.8-fold increased in eNOStg*ApoE KO mice as compared to ApoE KO mice (P<0.001, n=10). Transplantation of both WT- or eNOStg*ApoE KO BM-MNC in ApoE KO recipients caused a 1.6- to 2-fold increase in tissue perfusion and vessel density compared to PBS (P<0.01, n=10), while transplantation of ApoE KO BM-MNC had no positive effect on neovascularization. Moreover, transplantation of WT BM-MNC significantly increased plaque size, while eNOStg*ApoE KO BM-MNC had no effect on plaque size. eNOS overexpression did not affect BM-MNC apoptosis and secretion of growth factors but increased their ability to differentiate in vitro into EPC. Conclusion: eNOS overexpression in the endothelium improves post-ischemic neovascularization in both physiological as atherosclerotic settings. Furthermore, eNOS overexpression in the bone marrow restores the impaired pro-angiogenic potential of atherosclerotic BM-MNC without adverse effects on plaque size. Therefore, overexpression of eNOS could play a vital part in the development of therapeutic angiogenesis for atherosclerotic disease.

scholarly journals Protection against graft vs. host-associated immunosuppression in F1 mice. I. Activation of F1 regulatory cells by host-specific anti-major histocompatibility complex antibodies.

1981 ◽  
Vol 154 (6) ◽  
pp. 1922-1934 ◽  
Author(s):  
U Hurtenbach ◽  
D H Sachs ◽  
G M Shearer
Keyword(s):  
Major Histocompatibility Complex ◽  
Cytotoxic T Lymphocyte ◽  
Major Histocompatibility ◽  
Spleen Cells ◽  
Cell Surface Antigens ◽  
F1 Hybrid ◽  
Histocompatibility Complex ◽  
Parental Haplotype ◽  
Ctl Responses

Injection of parental spleen cells into unirradiated F1 hybrid mice results in suppression of the potential to generate cytotoxic T lymphocyte (CTL) responses in vitro. In an attempt to protect the F1 mice from immunosuppression, the recipients were injected with antibodies specific for major histocompatibility complex (MHC)-encoded antigens of the F1 mice 24 h before inoculation of the parental spleen cells. 8-14 d later, the generation of CTL responses in vitro against H-2 alloantigens was tested. Alloantiserum directed against either parental haplotype of the F1 strain markedly diminished the suppression of CTL activity. Furthermore, monoclonal antibodies recognizing H-2 or Ia antigens protected the F2 mice from parental spleen cell-induced suppression. Although this study has been limited to reagents that recognize host H-2 determinants, these findings do not necessarily imply that protection against graft vs. host (GvH) can be achieved only with anti-MHC antibodies. However, protection was observed only by antibodies reactive with F1 antigens, and small amounts of the alloantibodies were sufficient to diminish CTL suppression. Adoptive transfer of spleen cells from syngeneic F1 mice treated with anti-h-2a alloantiserum 24 h previously provided protection equal to that of injection of the recipients with alloantibodies. The cells necessary for this effect were shown to be T cells and to be radiosensitive to 2000 rad. This cell population is induced by antisera against F1 cell surface antigens and effectively counteracts GvH-associated immuno-suppression.

scholarly journals Regulation of a Graft-Versus-Leukemia Effect by Major Histocompatibility Complex Class II Molecules on Leukemia Cells: HLA-DR1 Expression Renders K562 Cell Tumors Resistant to Adoptively Transferred Lymphocytes in Severe Combined Immunodeficiency Mice/Nonobese Diabetic Mice

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4553-4558 ◽  
Author(s):  
Frank F. Weichold ◽  
Yin-zheng Jiang ◽  
Daniel E. Dunn ◽  
Michael Bloom ◽  
Vera Malkovska ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Nod Mice ◽  
Class Ii ◽  
Leukemia Cells ◽  
Combined Immunodeficiency ◽  
Histocompatibility Complex ◽  
Proliferation In Vitro

Abstract To understand the role of key molecules in determining the strength and nature of allogeneic T-cell response to leukemia, we transfected HLA-DR1 into the major histocompatibility complex (MHC)-deficient, natural killer (NK)-cell sensitive K562 leukemia cell line. Untransfected K562 cells stimulated NK proliferation in vitro and formed subcutaneous tumors in severe combined immunodeficiency/non-obese diabetic (SCID/NOD) mice. Tumor growth was inhibited by adoptive intravenous transfer of fresh unprimed peripheral blood mononuclear cells (PBMC). In contrast, HLA-DR1 transfected cells stimulated CD4+ T cells, but not NK-cell proliferation in vitro and formed tumors resistant to fresh PBMC in SCID/NOD mice. Tumors not expressing MHC were infiltrated with CD16+CD56+ lymphocytes whereas nonregressing HLA-DR1 expressing tumors showed only a scanty infiltration with both T-cell and NK-cell subsets. The results indicate that MHC class II expression by leukemia cells can determine the effector cell type that it engages. In vivo MHC class II expression rendered K562 cell tumors resistant to NK-cell mediated antitumor reactivity.

scholarly journals Administration of recombinant human interleukin-7 alters the frequency and number of myeloid progenitor cells in the bone marrow and spleen of mice

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1121-1129 ◽  
Author(s):  
G Damia ◽  
KL Komschlies ◽  
CR Faltynek ◽  
FW Ruscetti ◽  
RH Wiltrout
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Fold Increase ◽  
Peripheral Blood Lymphocytes ◽  
Lymphoid Cells ◽  
Blood Leukocytes ◽  
Interleukin 7 ◽  
Immature B Cells ◽  
Myeloid Progenitor Cells ◽  
Phenotype Analysis

Abstract The administration of greater than or equal to 5 micrograms interleukin- 7 (IL-7) twice a day to mice for 4 to 7 days increased by twofold to fivefold the total number of splenic and peripheral blood leukocytes, but did not appreciably increase bone marrow (BM) cellularity. This regimen of IL-7 administration also resulted in a greater than 90% reduction in the frequency and total number of single lineage colony- forming unit-culture (CFU-c) and multilineage CFU-granulocyte, erythroid, monocyte, megakaryocyte colonies that could be cultured from the BM, but a fivefold to 15-fold increase in the number of these progenitors that could be cultured from the spleen. All of these effects were reversible with progenitor and white blood cell numbers returning to near normal by day 6. Morphologic analysis of cells obtained from the BM of IL-7-treated mice showed an increase in lymphoid cells. Surface phenotype analysis showed that most of this IL- 7-induced increase in lymphocytes was attributable to an increase in immature B cells (B220+, sIg-), while cells expressing the myelomonocytic markers 8C5 and MAC-1 decreased by twofold to threefold. Further studies showed that the administration of IL-7 to mice that had been rendered leukopenic by the injection of cyclophosphamide (Cy) or 5- fluorouracil (5FU) exhibited a more rapid recovery and/or overshoot in their peripheral blood lymphocytes when compared with mice treated with Cy or 5FU alone. These results show that IL-7 can differentially regulate myelopoiesis in the BM and spleen, while stimulating lymphopoiesis.

scholarly journals Long-term generation and expansion of human primitive hematopoietic progenitor cells in vitro

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 661-669 ◽  
Author(s):  
EF Srour ◽  
JE Brandt ◽  
RA Briddell ◽  
S Grigsby ◽  
T Leemhuis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Fold Increase ◽  
Hematopoietic Progenitor Cells ◽  
Proliferative Potential ◽  
Hematopoietic Progenitor ◽  
Hla Dr

Abstract Although sustained production of committed human hematopoietic progenitor cells in long-term bone marrow cultures (LTBMC) is well documented, evidence for the generation and expansion of human primitive hematopoietic progenitor cells (PHPC) in such cultures is lacking. For that purpose, we attempted to determine if the human high proliferative potential colony-forming cell (HPP-CFC), a primitive hematopoietic marrow progenitor cell, is capable of generation and expansion in vitro. To that effect, stromal cell-free LTBMC were initiated with CD34+ HLA-DR-CD15- rhodamine 123dull bone marrow cells and were maintained with repeated addition of c-kit ligand and a synthetic interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein. By day 21 of LTBMC, a greater than twofold increase in the number of assayable HPP-CFC was detected. Furthermore, the production of HPP-CFC in LTBMC continued for up to 4 weeks, resulting in a 5.5-fold increase in HPP-CFC numbers. Weekly phenotypic analyses of cells harvested from LTBMC showed that the number of CD34+ HLA-DR- cells increased from 10(4) on day 0 to 56 CD34+ HLA-DR- cells increased from 10(4) on day 0 to 56 x 10(4) by day 21. To examine further the nature of the in vitro HPP-CFC expansion, individual HPP- CFC colonies were serially cloned. Secondary cloning of individual, day 28 primary HPP-CFC indicated that 46% of these colonies formed an average of nine secondary colony-forming unit--granulocyte-macrophage (CFU-GM)--derived colonies, whereas 43% of primary HPP-CFC gave rise to between one and six secondary HPP-CFC colonies and 6 to 26 CFU-GM. These data show that CD34+ HLA-DR- CD15- rhodamine 123dull cells represent a fraction of human bone marrow highly enriched for HPP-CFC and that based on their regeneration and proliferative capacities, a hierarchy of HPP-CFC exists. Furthermore, these studies indicate that in the presence of appropriate cytokine stimulation, it is possible to expand the number of PHPC in vitro.

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