scholarly journals Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2216-2223 ◽  
Author(s):  
RJ Soiffer ◽  
R Gonin ◽  
C Murray ◽  
MJ Robertson ◽  
K Cochran ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cd8 T Cells ◽  
Odds Ratio ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Cd8 Cells ◽  
Graft Versus Host ◽  
Marrow Infusion

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2–4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had < or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and < or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2–4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.

scholarly journals Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2216-2223 ◽  
Author(s):  
RJ Soiffer ◽  
R Gonin ◽  
C Murray ◽  
MJ Robertson ◽  
K Cochran ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cd8 T Cells ◽  
Odds Ratio ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Cd8 Cells ◽  
Graft Versus Host ◽  
Marrow Infusion

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2–4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had < or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and < or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2–4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.

scholarly journals Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4097-4104 ◽  
Author(s):  
Yanhui Xu ◽  
Andrew S. Flies ◽  
Dallas B. Flies ◽  
Gefeng Zhu ◽  
Sudarshan Anand ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Proliferative Potential ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells

Abstract Decoy lymphotoxin β receptor (LTβR) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LTβ-LTβR and LIGHT-HVEM/LTβR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti–host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti–HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.

scholarly journals Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1522-1529 ◽  
Author(s):  
Kai Sun ◽  
Minghui Li ◽  
Thomas J. Sayers ◽  
Lisbeth A. Welniak ◽  
William J. Murphy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
T Cell Subsets ◽  
Allogeneic Bone

Abstract Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4+ but not CD8+ T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFα but not IFNγ levels. Transfer of Tnf−/− T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8+ T cells resulted in enhanced GVT response, which was dependent on donor CD8+ T cell–derived IFNγ. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4+ T cells from the graft or by inhibiting TNFα.

Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2886-2895 ◽  
Author(s):  
Cornelius Schmaltz ◽  
Onder Alpdogan ◽  
Kirsten J. Horndasch ◽  
Stephanie J. Muriglan ◽  
Barry J. Kappel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Fas Ligand ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent → F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp−/− donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp−/− T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp−/− T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4+ or CD8+ donor T cells, the FasL pathway was important for GVHD activity by both CD4+ and CD8+ T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.

Donor T Cells Lacking IFN-Gamma Receptor Expression Enhance Donor Myeloid Engraftment and Decrease Early Acute Graft-Versus-Host Disease Mortality Following Allogeneic Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3514-3514
Author(s):  
Kai Sun ◽  
Minghui Li ◽  
Mark A. Hubbard ◽  
Lisbeth A. Welniak ◽  
William J. Murphy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Ifn Gamma ◽  
Graft Versus Host ◽  
Gamma Receptor ◽  
Donor T Cells

Abstract Lack of engraftment, graft-versus-host disease (GVHD) and tumor relapse are major issues that affect clinical outcome after allogeneic bone marrow transplantation (allo-BMT). Donor T cells in the graft present a dilemma in allo-BMT due to both the beneficial and deleterious clinical effects they can exert. Therefore, modulation of donor T cell function may represent a potential therapeutic approach in allo-BMT. In murine allo-BMT models, It has been demonstrated that donor T cell-derived IFN-gamma is required for optimal graft-versus-tumor (GVT) responses but it also plays complex roles by exhibiting both protective and pathogenic effects in GVHD development. We therefore investigated the role of IFN-gamma responsiveness by the donor T cells in allo-BMT through the use of IFN-gamma receptor deficient (IfnR−/−; RKO) mice. In these experiments, recipient BALB/c (H2d) mice received lethal total body irradiation. Irradiation was followed by the infusion of graded doses of T cell-depleted (TCD) allogeneic bone marrow cells (5 or 15 × 106) intravenously from major histocompatibility complex (MHC)-disparate wild type (WT) C57BL/6 (H2b, IfnR+/+) mice, with or without 0.5 × 106 T cells (or 3 × 106 splenocytes as a source of allogeneic T cells) from either WT (H2b, IfnR+/+) or RKO mice. Compared with transplantation of WT TCD-BMCs with T cells from a WT donor, we found that transplantation of WT TCD-BMCs with RKO T cells resulted in marked and significant increases in myeloid engraftment as determined by CFU-GM, peripheral neutrophil and platelet counts during the early phase of allo-BMT. Consistently, a significant increase serum G-CSF was also found on day 7 after allo-BMT with this group. This enhanced myeloid engraftment by RKO T cells occurred only in murine allo-BMT but not syngeneic BMT models, indicating it is a property of alloreactivity. Interestingly, no significant differences in donor T cell engraftment, nor in the percentage of Treg, Th17, CD4+ or CD8+ T cell subsets and IFN-gamma+ T cells, were observed in spleen. However, on day 7 after allo-BMT, significantly fewer donor T cells were observed in the gut in the recipient of RKO T cells compared to recipients of WT T cells. This reduction of donor T cells in gut was associated with a significant decrease in early acute GVHD lethality. This novel finding suggests transplantation of T cells lacking IFN-gamma receptors resulted in less donor T cell homing to the gut during the early phase of allo-BMT. We next addressed the ability of donor RKO T cells to provide GVT responses. A20 tumor-bearing BALB/c (H2d) mice were transplanted with WT C57BL/6 TCD-BMC. Compared with transplantation of 1 × 106 WT T cells with WT TCD-BMC, co-transplantation of 1 × 106 RKO T cells with WT TCD-BMC resulted in less GVHD-related mortality with greater anti-tumor effects. Taken together, these observations suggest that targeting IFN-gamma receptor signaling on donor T cells may help to improve the efficacy of allo-BMT by promoting donor myeloid engraftment and decreasing early acute GVHD lethality with greater GVT potential due to altered lymphocyte homing.

scholarly journals Clonally Expanded CD8+ T cells in Allogeneic Bone Marrow Transplantation

2008 ◽  
Vol 59 (6) ◽  
pp. 635-636
Author(s):  
T. M. Kollgaard ◽  
S. Reker ◽  
S. L. Petersen ◽  
T. N. Masmas ◽  
L. L. Vindelov ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone

scholarly journals Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1574-1580 ◽  
Author(s):  
Robert R. Jenq ◽  
Christopher G. King ◽  
Christine Volk ◽  
David Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Effector Cells ◽  
Cd8 Cells ◽  
T Cell Reconstitution ◽  
Dna Plasmid

Abstract Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.

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