Development of T cells in SCID mice grafted with fetal thymus from AKR mice or F344 rats

The search for human hematopoietic stem cells has been hampered by the lack of appropriate assay systems. Demonstration of the ability of precursor cell candidates to give rise to T cells is of significant difficulty since dissociated in vitro cultured thymus stroma cells lose their ability to sustain thymocyte maturation. To define further the differentiative capacities of the rare human fetal liver and bone marrow cells that express the CD34 surface antigen and exhibit in vitro myeloid and pre-B cell activities, we have microinjected them into HLA-mismatched fetal thymus fragments, partially depleted of hematopoietic cells by low temperature culture. In vitro colonized thymuses have then been allowed to develop upon engraftment into immunodeficient SCID mice. Using this modification of the SCID-hu system, we show that low numbers of fetal CD34+ progenitor cells can repopulate the lymphoid compartment in the human thymus.

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Development of Functional Rat-Derived T Cells in SCID Mice Engrafted with the Fetal Thymus of LEC Rats Which Are Defective in CD4+T Cells

Microbiology and Immunology ◽

10.1111/j.1348-0421.1996.tb01124.x ◽

1996 ◽

Vol 40 (9) ◽

pp. 659-664 ◽

Cited By ~ 2

Author(s):

Jian-Guo Chai ◽

Tohru Sakai ◽

Hajime Hisaeda ◽

Hideyuki Nagasawa ◽

Koji Yasutomo ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Scid Mice ◽

Fetal Thymus ◽

Lec Rats

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The concurrent maturation of mouse and human thymocytes in human fetal thymus implanted in NIH-beige-nude-xid mice is associated with the reconstitution of the murine immune system.

Journal of Experimental Medicine ◽

10.1084/jem.177.3.821 ◽

1993 ◽

Vol 177 (3) ◽

pp. 821-832 ◽

Cited By ~ 9

Author(s):

T R Kollmann ◽

M M Goldstein ◽

H Goldstein

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Keyhole Limpet Hemocyanin ◽

Cell Receptor ◽

Scid Mice ◽

Double Positive ◽

Fetal Thymus

To determine whether the human thymus provides an environment for the maturation of murine T cells, human fetal thymus and liver (hu-thy/liv) were implanted into congenitally athymic NIH-beige-nude-xid (BNX) mice or C.B-17 scid/scid (SCID) mice. 3 mo after implantation, in contrast to the hu-thy/liv implant in SCID mice, which was populated only with human CD4/CD8 single- and double-positive thymocytes, the hu-thy/liv implant in BNX mice contained a chimeric population of human and mouse CD4/CD8 single- and double-positive thymocytes. Immunohistochemical staining of the hu-thy/liv implant in BNX mice indicated that the population of double-positive mouse thymocytes was localized to discrete areas of the human fetal thymus. Quantitative improvements in mouse T cell and immunoglobulin (Ig) G parameters were observed after grafting of the human fetal thymus and liver tissue into BNX mice. In addition, in contrast to the nonimplanted BNX mice, the implanted BNX mice were capable of mounting a keyhole limpet hemocyanin-specific IgG response and their peripheral T cells were responsive to stimulation with mitogens and antibodies directed to the T cell receptor. Furthermore, after in vivo priming, T cells present in lymph nodes of the implanted BNX mice were capable of mounting an antigen-induced in vitro T cell-dependent proliferative response. Thus, concurrent with the continued maturation of human T cells, murine T cells differentiated within the human fetal thymus implanted in the BNX mice and mediated the phenotypic and functional reconstitution of the murine immune system. Mice with a reconstituted immune system that contain a human thymic implant that is infectible with human immunodeficiency virus (HIV) should prove useful in the investigation of T cell maturation in the thymus and in the evaluation of potential HIV vaccines.

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Enhanced thymic development in SCID mice in the presence of allogeneic T cells

Immunology Letters ◽

10.1016/s0165-2478(97)87159-3 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 82

Author(s):

M Schneider

Keyword(s):

T Cells ◽

Scid Mice ◽

Thymic Development

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In vitro differentiation of human fetal thymus, cord blood, and peripheral blood CD4+ T cells into IL-10-producing T cells: Implications for transplantation tolerance

Immunology Letters ◽

10.1016/s0165-2478(97)88270-3 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 354

Author(s):

T Sornasse

Keyword(s):

T Cells ◽

Cord Blood ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Transplantation Tolerance ◽

In Vitro Differentiation ◽

Fetal Thymus

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CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00962.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. H689-H697 ◽

Cited By ~ 30

Author(s):

Karen Y. Stokes ◽

LeShanna Calahan ◽

Candiss M. Hamric ◽

Janice M. Russell ◽

D. Neil Granger

Keyword(s):

Oxidative Stress ◽

T Cells ◽

T Cell ◽

Blood Cell ◽

Cell Function ◽

Inflammatory Responses ◽

Microvascular Dysfunction ◽

Cd40 Ligand ◽

Scid Mice ◽

Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

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T cell-independent antibody-mediated clearance of polyoma virus in T cell-deficient mice.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.403 ◽

1996 ◽

Vol 183 (2) ◽

pp. 403-411 ◽

Cited By ~ 73

Author(s):

E Szomolanyi-Tsuda ◽

R M Welsh

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Nude Mice ◽

Knockout Mice ◽

Cell Receptor ◽

Genetically Engineered ◽

Scid Mice ◽

Myeloproliferative Disease ◽

Alpha Beta

Polyomavirus (PyV) infection of SCID mice, which lack functional T and B cells, leads to a lethal acute myeloproliferative disease (AMD) and to high levels of virus replication in several organs by two wk after infection. This is in contrast to infection of T cell-deficient athymic nude mice, which are resistant to acute PyV-induced disease and poorly replicate the virus in their organs. This major difference in the virus load and in the outcome of PyV infection between SCID and nude mice suggested that an efficient, T cell-independent antiviral mechanism operates in T cell-deficient, PyV infected mice. To investigate this possibility, mice with different genetically engineered T and/or B cell deficiencies and SCID mice adoptively reconstituted with B and/or T cells were infected with PyV. The results indicated that the presence of B cells in the absence of T cells protected mice from the AMD, and this was accompanied by a major reduction of PyV in all organs tested. Sera from PyV-infected T cell receptor (TCR) alpha beta knockout or TCR alpha beta gamma delta knockout mice contained IgG2a antibodies to PyV. Sera or purified immunoglobulin fractions from PyV-infected TCR alpha beta knockout mice protected SCID mice from the PyV-induced AMD. To our knowledge, this is the first report of an effective T cell-independent antibody response clearing a virus and changing the outcome of infection from 100% mortality to 100% survival.

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Intra-thymic/splenic engraftment of human T cells in HLA-DR1 transgenic NOD/scid mice

Cellular Immunology ◽

10.1016/j.cellimm.2005.02.003 ◽

2004 ◽

Vol 232 (1-2) ◽

pp. 86-95 ◽

Cited By ~ 6

Author(s):

Ramon E. Camacho ◽

Richard Wnek ◽

Kashmira Shah ◽

Dennis M. Zaller ◽

Richard J. O’Reilly ◽

...

Keyword(s):

T Cells ◽

Scid Mice ◽

Human T Cells

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Lymphoid and myeloid differentiation of fetal liver CD34+lineage- cells in human thymic organ culture.

Journal of Experimental Medicine ◽

10.1084/jem.180.1.123 ◽

1994 ◽

Vol 180 (1) ◽

pp. 123-132 ◽

Cited By ~ 53

Author(s):

A Bárcena ◽

A H Galy ◽

J Punnonen ◽

M O Muench ◽

D Schols ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Organ Culture ◽

Nk Cells ◽

Progenitor Cells ◽

Fetal Liver ◽

Myeloid Differentiation ◽

Target Cells ◽

Hematopoietic Progenitors ◽

Fetal Thymus

In this article, we report that the human fetal thymus contains CD34bright cells (< 0.01% of total thymocytes) with a phenotype that resembles that of multipotent hematopoietic progenitors in the fetal bone marrow. CD34bright thymocytes were CD33-/dull and were negative for CD38, CD2, and CD5 as well as for the lineage markers CD3, CD4, and CD8 (T cells), CD19 and CD20 (B cells), CD56 (NK cells), glycophorin (erythrocytes), and CD14 (monocytes). In addition, total CD34+ lineage negative (lin-) thymocytes contained a low number of primitive myeloid progenitor cells, thus suggesting that the different hematopoietic lineages present in the thymus may be derived from primitive hematopoietic progenitor cells seeding the thymus. To investigate whether the thymus is permissive for the development of non-T cells, human fetal organ culture (FTOC) assays were performed by microinjecting sorted CD34+lin- fetal liver cells into fragments of HLA-mismatched fetal thymus. Sequential phenotypic analysis of the FTOC-derived progeny of CD34+lin- cells indicated that the differentiation into T cells was preceded by a wave of myeloid differentiation into CD14+CD11b+CD4dull cells. Donor-derived B cells (CD19+CD20+) were also generated, which produced immunoglobulins (IgG and IgM) when cultured under appropriate conditions, as well as functional CD56+CD3- NK cells, which efficiently killed K562 target cells in cytotoxicity assays. These results demonstrate that the microinjection of fetal liver hematopoietic progenitors into fetal thymic organ fragments results in multilineage differentiation in vitro.

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