Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Jonathan S. Serody ◽  
Donald N. Cook ◽  
Suzanne L. Kirby ◽  
Elizabeth Reap ◽  
Thomas C. Shea ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Class I ◽  
Wild Type ◽  
Inhibitory Protein ◽  
Host Disease ◽  
Graft Versus Host

Abstract The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.

Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Jonathan S. Serody ◽  
Donald N. Cook ◽  
Suzanne L. Kirby ◽  
Elizabeth Reap ◽  
Thomas C. Shea ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Class I ◽  
Wild Type ◽  
Inhibitory Protein ◽  
Host Disease ◽  
Graft Versus Host

The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P < .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P < .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Abstract Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P &lt; .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P &lt; .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

Host Plasmacytoid or Conventional Dendritic Cells Alone Are Sufficient To Initiate Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2164-2164
Author(s):  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Kazutoshi Aoyama ◽  
Ken-ichi Matsuoka ◽  
Kennosuke Karube ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Alloantigen expression on host dendritic cells (DCs) is critical to initiate GVHD. DCs can be divided into two main subpopulations; conventional DCs (cDCs) and plasmacytoid DCs (pDCs), however, the contribution of each DC subset to elicit GVHD remains unclear. We examined the ability of cDCs and pDCs to initiate GVHD. pDCs, cDCs and B cells were isolated from C57BL/6 (B6: H–2b) mice treated with Flt3 ligand in order to expand DCs. pDCs were enriched from bone marrow by depleting CD3+, CD19+, CD11b+, and CD49b+ cells, followed by a FACS sorting of CD11cint B220+ cells. cDCs and B cells were sorted from splenocytes as CD11chi B220− cells and CD11c− B220+ cells, respectively. Isolated pDCs showed plasmacytoid morphology, produced IFN-α in response to CpG oligonucleotide. Although pDCs stimulated allogeneic T cells far less potently than cDCs, stimulation with CpG enhanced their allostimulatory capacity as potent as cDCs. We compared the ability of each DC subset to initiate GVHD by an add-back study of MHC class II-expressing DCs into MHC class II-deficient (II−/−) mice that were resistant to CD4-dependent GVHD. Lethally irradiated II−/− B6 mice were injected with 2 × 106 pDCs, cDCs or B cells from wild-type (II+/+) B6 mice on day -1 and injected with 2 × 106 CD4+ T cell from BALB/c (H–2d) mice on day 0. A flow cytometric analysis of the mesenteric lymph nodes on day +5 demonstrated significantly greater expansion of donor CD4+ T cells in recipients of pDCs or cDCs than those of B cells (Table). While injection of B cells did not cause any sign of GVHD, injection of pDCs or cDCs alone was sufficient to produce clinical and pathological GVHD (Table), thus breaking GVHD resistance of II−/− mice. We next examined the ability of pDCs to induce CD8-dependent GVHD in MHC-matched transplant using mice deficient in functional MHC class I expression (β2m−/−). Again, injection of pDCs or cDCs alone was sufficient to cause expansion of donor CD8+ T cells (p&lt;0.05). We next asked whether signaling through Toll-like receptors (TLRs) could be required for pDCs to initiate GVHD. However, injection of pDCs isolated from MyD88/TRIF-double deficient mice was able to initiate GVHD as potent as wild-type pDCs, thus demonstrating that pDCs initiate GVHD in a TLR signaling independent manner. These results provide important information for developing strategies aimed at inactivating host DCs to prevent GVHD. Impact of each APC subpopulation on GVHD APC Donor CD4 expansion (×103±SE) Clinical GVHD score (mean±SE) Pathological GVHD score (mean±SE) *p&lt;0.05 compared with B cells B cell 0.1 ± 0.0 2.1 ± 0.2 2.1 ± 0.2 pDC 5.3 ± 2.4* 4.3 ± 0.3* 7.4 ± 0.5* cDC 9.7 ± 3.8 * 3.8 ± 0.5 * 7.2 ± 0.7*

T-lymphocyte production of macrophage inflammatory protein-1α is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 2973-2980 ◽  
Author(s):  
Jonathan S. Serody ◽  
Susan E. Burkett ◽  
Angela Panoskaltsis-Mortari ◽  
Judith Ng-Cashin ◽  
Eileen McMahon ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Class I ◽  
Wild Type ◽  
Host Disease ◽  
Graft Versus Host ◽  
Inflammatory Protein ◽  
Donor T Cells ◽  
Macrophage Inflammatory Protein

To investigate the mechanism by which macrophage inflammatory protein-1α (MIP-1α) affects graft-versus-host disease (GVHD), the expression and function of MIP-1α in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1α was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1α were transferred, there was a decrease in the production of MIP-1α in the liver, lung, and spleen of bm1 (B6.C-H2bm1/By) and bm12 (B6.C-H2bm12/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8+ T cells in the lung and approximately a 2-fold decrease in the number of CD8+ T cells in the liver and spleen in bm1 recipients after transfer of MIP-1α–deficient (MIP-1α−/−) splenocytes compared to wild-type (MIP-1α+/+) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4+ T cells found in the liver and lung was significantly increased after the transfer of MIP-1α−/− compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1α in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8+, but not CD4+, donor T cells. Production of MIP-1α by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.

scholarly journals Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 749-755 ◽  
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Chen Liu ◽  
Dennis Keith Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Γδ T Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P &lt; .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

The Role of Autoreactive T Lymphocytes in Graft-versus-Host Disease (GVHD)

1988 ◽  
pp. 158-160
Author(s):  
Robertson Parkman ◽  
Josette Champagne ◽  
Maxwell Cooper ◽  
Veronica Draper ◽  
Yves DeClerck ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host

scholarly journals Inhibition of nitric oxide production is associated with enhanced weight loss, decreased survival, and impaired alloengraftment in mice undergoing graft-versus-host disease after bone marrow transplantation

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2363-2373 ◽  
Author(s):  
WR Drobyski ◽  
CA Keever ◽  
GA Hanson ◽  
T McAuliffe ◽  
OW Griffith
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Weight Loss ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
No Production ◽  
Host Disease ◽  
Graft Versus Host

The pathophysiologic role of nitric oxide (NO) in graft-versus-host disease (GVHD) was investigated in a murine bone marrow (BM) transplantation model where donor and recipient were H-2-matched but differed at multiple minor histocompatibility antigens. Host AKR/J (H- 2K) mice received lethal total body irradiation as pretransplant conditioning followed by transplantation of donor B10.BR (H-2K) BM cells with or without spleen cells as a source of GVH-reactive T cells. NO production, as assessed by serum nitrate and nitrite levels, was increased for up to 3 weeks posttransplant in animals undergoing both moderate and severe GVHD. Administration of NG-methyl-L-arginine (L- NMA), an inhibitor of nitric oxide synthase, to animals undergoing GVHD resulted in effective suppression of NO production when compared with saline-treated GVHD control animals. Suppression of NO production by L- NMA in GVHD animals was associated with enhanced weight loss early posttransplant and decreased overall survival. Histologic analysis of tissues from L-NMA-treated and saline-treated GVHD animals showed that early weight loss was not because of an exacerbation of GVHD, indicating that NO did not appear to play an immunosuppressive role in this experimental model. L-NMA-treated animals with enhanced weight loss were observed to have splenic atrophy, decreased extramedullary hematopoiesis, and a reduction in BM cellularity when compared with GVHD control mice that were weight-matched before transplant. Analysis of T-cell chimerism in the spleen showed that L-NMA treatment impaired donor T-cell repopulation. In vitro colony-forming unit (CFU) assays were performed to further assess the role of NO on BM progenitor cell growth. L-NMA added directly into culture had no effect on CFU- granulocyte/macrophage (CFU-GM) formation in normal murine BM. In contrast, total CFU-GM from L-NMA-treated animals were significantly reduced when compared with GVHD controls or BM control animals who did not develop GVHD. Collectively, these data indicate that inhibition of NO impairs hematopoietic reconstitution and support the premise that NO appears to play a novel role in the facilitation of alloengraftment posttransplant.

scholarly journals INVOLVEMENT OF IL-2Rβ+ T CELLS IN GRAFT-VERSUS-HOST DISEASE OF THE LIVER AND INTESTINE ACROSS MUTANT MHC CLASS I OR CLASS II BARRIER

1998 ◽  
Vol 19 (1) ◽  
pp. 9-19 ◽  
Author(s):  
KATSUHIKO HASEGAWA ◽  
SHUHJI SEKI ◽  
SATOSHI YAMAGIWA ◽  
KAZUNARI SATO ◽  
SATOSHI SUGAHARA ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Class I ◽  
Host Disease ◽  
Graft Versus Host
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