Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart

2016 ◽  
Vol 30 (9) ◽  
pp. 3069-3082 ◽  
Author(s):  
Xi‐Ping Huang ◽  
Ana Ludke ◽  
Sanjiv Dhingra ◽  
Jian Guo ◽  
Zhuo Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Stem Cells ◽  
Allogeneic Bone ◽  
Immune Rejection ◽  
Class Ii Transactivator ◽  
Histocompatibility Complex ◽  
Infarcted Heart ◽  
Major Histocompatibility Complex Ii

scholarly journals Major Histocompatibility Complex Restriction Between Hematopoietic Stem Cells and Stromal Cells In Vivo

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Futoshi Hashimoto ◽  
Kikuya Sugiura ◽  
Kyoichi Inoue ◽  
Susumu Ikehara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Graft Failure ◽  
Major Histocompatibility ◽  
Hematopoietic Stem ◽  
Histocompatibility Complex ◽  
Colony Forming Units

Graft failure is a mortal complication in allogeneic bone marrow transplantation (BMT); T cells and natural killer cells are responsible for graft rejection. However, we have recently demonstrated that the recruitment of donor-derived stromal cells prevents graft failure in allogeneic BMT. This finding prompted us to examine whether a major histocompatibility complex (MHC) restriction exists between hematopoietic stem cells (HSCs) and stromal cells. We transplanted bone marrow cells (BMCs) and bones obtained from various mouse strains and analyzed the cells that accumulated in the engrafted bones. Statistically significant cell accumulation was found in the engrafted bone, which had the same H-2 phenotype as that of the BMCs, whereas only few cells were detected in the engrafted bones of the third-party H-2 phenotypes during the 4 to 6 weeks after BMT. Moreover, the BMCs obtained from the MHC-compatible bone showed significant numbers of both colony-forming units in culture (CFU-C) and spleen colony-forming units (CFU-S). These findings strongly suggest that an MHC restriction exists between HSCs and stromal cells.

scholarly journals Major Histocompatibility Complex Restriction Between Hematopoietic Stem Cells and Stromal Cells In Vivo

Blood ◽  
1997 ◽  
Vol 89 (1) ◽  
pp. 49-54 ◽  
Author(s):  
Futoshi Hashimoto ◽  
Kikuya Sugiura ◽  
Kyoichi Inoue ◽  
Susumu Ikehara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Graft Failure ◽  
Major Histocompatibility ◽  
Hematopoietic Stem ◽  
Histocompatibility Complex ◽  
Colony Forming Units

Abstract Graft failure is a mortal complication in allogeneic bone marrow transplantation (BMT); T cells and natural killer cells are responsible for graft rejection. However, we have recently demonstrated that the recruitment of donor-derived stromal cells prevents graft failure in allogeneic BMT. This finding prompted us to examine whether a major histocompatibility complex (MHC) restriction exists between hematopoietic stem cells (HSCs) and stromal cells. We transplanted bone marrow cells (BMCs) and bones obtained from various mouse strains and analyzed the cells that accumulated in the engrafted bones. Statistically significant cell accumulation was found in the engrafted bone, which had the same H-2 phenotype as that of the BMCs, whereas only few cells were detected in the engrafted bones of the third-party H-2 phenotypes during the 4 to 6 weeks after BMT. Moreover, the BMCs obtained from the MHC-compatible bone showed significant numbers of both colony-forming units in culture (CFU-C) and spleen colony-forming units (CFU-S). These findings strongly suggest that an MHC restriction exists between HSCs and stromal cells.

scholarly journals Prevention of graft-versus-host disease by peptides binding to class II major histocompatibility complex molecules

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2802-2810 ◽  
Author(s):  
PG Schlegel ◽  
R Aharoni ◽  
DE Smilek ◽  
LP Fernandez ◽  
HO McDevitt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Major Histocompatibility ◽  
Complex Molecules ◽  
Host Disease ◽  
Graft Versus Host ◽  
Histocompatibility Complex

Abstract Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1–11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin- 5 gene.

Major histocompatibility complex–mismatched allogeneic bone marrow transplantation using perforin and/or Fas ligand double-defective CD4+ donor T cells: involvement of cytotoxic function by donor lymphocytes prior to graft-versus-host disease pathogenesis

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 390-397 ◽  
Author(s):  
Zhe Jiang ◽  
Eckhard Podack ◽  
Robert B. Levy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Fas Ligand ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Donor T Cells ◽  
Cytotoxic Function

Experimental allogeneic bone marrow transplantation (BMT) models using cytotoxic single-deficient (perforin/granzyme or Fas ligand [FasL]) and cytotoxic double-deficient (cdd) CD4+donor T cells have previously demonstrated roles for both effector pathways in graft-versus-host disease (GVHD). In the present study, the role of CD4-mediated antihost cytotoxicity in a GVH response is further examined across a complete major histocompatibility complex class I/II mismatch. As predicted, a double cytotoxic deficiency resulted in a clear delay in GVH-associated weight loss, clinical changes, and mortality. Interestingly, analysis of donor T-cell presence in 5.5-Gy recipients soon after BMT demonstrated that the double cytotoxic deficiency resulted in a marked decrease in donor CD4 numbers. Transplantation of singularly perforin- or FasL-deficient donor CD4+ T cells demonstrated that the absence of FasL was responsible for the markedly diminished CD4 number in recipient lymph nodes and spleens soon after BMT. However, increasing recipient total body irradiation conditioning (11.0 Gy) abrogated the decrease in FasL-defective B6-cdd and B6-gld CD4 numbers. Thus, the decrease was not a result of inherent CD4 defects, but was probably attributable to host resistance. Consistent with these observations, transplantation into 11.0-Gy recipients resulted in identical GVH lethality by equal numbers of B6 wild-type, B6-cdd, and B6-gld CD4+ T-cell inoculum. In total, the findings indicate that aggressive host conditioning lessens the requirement for donor CD4+ cytotoxic function in GVH responses soon after BMT. The present results thus support the notion of a role for cytotoxic effector function in donor CD4+ T cells prior to GVH-induced tissue injury.

scholarly journals Profound atrophy of the bone marrow reflecting major histocompatibility complex class II-restricted destruction of stem cells by CD4+ cells.

1994 ◽  
Vol 180 (1) ◽  
pp. 307-317 ◽  
Author(s):  
J Sprent ◽  
C D Surh ◽  
D Agus ◽  
M Hurd ◽  
S Sutton ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class Ii ◽  
Complex Class ◽  
Cd4 Cells ◽  
Hemopoietic Cells ◽  
Histocompatibility Complex

The effector functions of CD4+ cells in vivo are presumed to reflect a combination of lymphokine-mediated bystander reactions and direct cytotoxic T lymphocyte activity. To assess the relative importance of these two mechanisms, we studied the effects of transferring small doses of purified unprimed CD4+ cells to lightly irradiated (600 cGy) recipients expressing major histocompatibility complex class II (Ia) differences. Within the first week after transfer, the host marrow was rapidly repopulated with hemopoietic cells. Thereafter, however, the donor CD4+ cells caused massive destruction of hemopoietic cells, both in marrow and spleen. Marrow aplasia did not affect stromal cells and was prevented by coinjecting donor but not host bone marrow. The use of allotypic markers and fluorescence-activated cell sorter analysis indicated that the destructive effects of CD4+ cells were directed selectively to host Ia+ hemopoietic cells, including stem cells; donor hemopoietic cells and Ia- host T cells were spared. No evidence could be found that the ongoing destruction of host cells impaired the capacity of donor stem cells to repopulate marrow, spleen, or thymus. Moreover, CD4+ cells failed to destroy host-type hemopoietic cells from Ia-deficient mice. Tissue destruction by CD4+ cells thus did not seem to reflect a bystander reaction. We conclude that, under defined conditions, CD4+ cells can manifest extremely potent Ia-restricted CTL activity in vivo, probably through recognition of covert Ia expression on stem cells and/or their immediate progeny.

scholarly journals Correcting metabolic deficits with allogeneic bone marrow stem cells in the cat

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Richard Vulliet ◽  
Mitch Halloran ◽  
Kelli Tallon ◽  
Leslie Lyons ◽  
Quinton Rogers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Stem Cells ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone

Irradiated Donor Leukocytes Promote Engraftment of Allogeneic Bone Marrow in Major Histocompatibility Complex Mismatched Recipients Without Causing Graft-Versus-Host Disease

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3222-3233 ◽  
Author(s):  
Edmund K. Waller ◽  
Alan M. Ship ◽  
Stephen Mittelstaedt ◽  
Timothy W. Murray ◽  
Richard Carter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Graft Versus Host Disease ◽  
Graft Rejection ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Donor T Cells

Abstract Graft rejection in allogeneic bone marrow transplantation (BMT) can occur when donor and recipient are mismatched at one or more major histocompatibility complex (MHC) loci. Donor T cells can prevent graft rejection, but may cause fatal graft-versus-host disease (GVHD). We tested whether irradiation of allogeneic donor lymphocytes would preserve their graft-facilitating activity while inhibiting their potential for GVHD. Infusions of irradiated allogeneic T cells did not cause GVHD in MHC-mismatched SJL → (SJL × C57BL6) F1, C57BL6 → B10.RIII, and C57BL6 → B10.BR mouse donor → recipient BMT pairs. The 60-day survival among MHC-mismatched transplant recipients increased from 2% (BM alone) to up to 75% among recipients of BM plus irradiated allogeneic splenocytes. Optimal results were obtained using 50 × 106 to 75 × 106 irradiated donor splenocytes administered in multiple injections from day −1 to day +1. Recipients of an equal number of nonirradiated MHC-mismatched donor splenocytes uniformly died of acute GVHD. The graft facilitating activity of the irradiated allogeneic splenocytes was mediated by donor T cells. Irradiation to 7.5 Gy increased nuclear NFκB in T cells and their allospecific cytotoxicity. Irradiated T cells survived up to 3 days in the BM of MHC-mismatched recipients without proliferation. Recipients of irradiated allogeneic splenocytes and allogeneic BM had stable donor-derived hematopoiesis without a significant representation of donor splenocytes in the T-cell compartment. Irradiated allogeneic T cells thus represent a form of cellular immunotherapy with time-limited biologic activity in vivo that can facilitate allogeneic BMT without causing GVHD.

Correction of a mouse model of sickle cell disease: lentiviral/antisickling β-globin gene transduction of unmobilized, purified hematopoietic stem cells

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4312-4319 ◽  
Author(s):  
Dana N. Levasseur ◽  
Thomas M. Ryan ◽  
Kevin M. Pawlik ◽  
Tim M. Townes
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Bone Marrow Stem Cells ◽  
Allogeneic Bone ◽  
Cell Disease ◽  
Long Term Treatment ◽  
Gene Therapy Protocol

AbstractAlthough sickle cell anemia was the first hereditary disease to be understood at the molecular level, there is still no adequate long-term treatment. Allogeneic bone marrow transplantation is the only available cure, but this procedure is limited to a minority of patients with an available, histocompatible donor. Autologous transplantation of bone marrow stem cells that are transduced with a stably expressed, antisickling globin gene would benefit a majority of patients with sickle cell disease. Therefore, the development of a gene therapy protocol that corrects the disease in an animal model and is directly translatable to human patients is critical. A method is described in which unmobilized, highly purified bone marrow stem cells are transduced with a minimum amount of self-inactivating (SIN) lentiviral vector containing a potent antisickling β-globin gene. These cells, which were transduced in the absence of cytokine stimulation, fully reconstitute irradiated recipients and correct the hemolytic anemia and organ pathology that characterize the disease in humans. The mean increase of hemoglobin concentration was 46 g/L (4.6 g/dL) and the average lentiviral copy number was 2.2; therefore, a 21-g/L /vector copy increase (2.1-g/dL) was achieved. This transduction protocol may be directly translatable to patients with sickle cell disease who cannot tolerate current bone marrow mobilization procedures and may not safely be exposed to large viral loads. (Blood. 2003;102:4312-4319)

Sign in / Sign up

Export Citation Format

Share Document