scholarly journals Telomerase Activity in Regulatory T Cells is Inversely Associated With Severity of Chronic Graft-Versus-Host Disease (cGVHD) After Hematopoietic Stem Cell Transplantation (HSCT)

2011 ◽  
Vol 17 (2) ◽  
pp. S325
Author(s):  
Y. Kawano ◽  
H.T. Kim ◽  
K.-I. Matsuoka ◽  
R. Smith ◽  
S. Lazo-Kallanian ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Telomerase Activity ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Inducible Costimulator (ICOS) Is up-Regulated in Dogs with Graft Versus Host Disease and Graft Rejection Following Non-Identical Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4109-4109
Author(s):  
Scott Stoll Graves ◽  
Masahiko Sato ◽  
Carol Loretz ◽  
Stone Diane ◽  
Rainer Storb
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract Abstract 4109 Inducible co-stimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4+ and CD8+ T-cells following their activation. Evidence suggests ICOS functions as an essential immune regulator and ICOS blockade is a potential target for allogeneic transplantation. We have used the canine model to develop several strategies for hematopoietic stem cell transplantation that have been successfully translated into the clinic. Here we describe the production and testing of monoclonal antibodies (mAb) directed against canine ICOS and determined the expression profile of ICOS in dogs. Canine ICOS was expressed in an inducible pattern on up to 89% of T-cells activated by Con A, anti-CD3 plus anti-CD28 mAb and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells obtained from dog leukocyte antigen nonidentical dogs. Significant augmentation of the immunosuppressive effects of ICOS blockade was observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig (CTLA4-Ig) or cyclosporine. ICOS expression was significantly up-regulated on T-cells collected from the peripheral blood, lymph nodes and spleen from dogs undergoing graft rejection or chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Dogs that remained mixed chimeric expressed ICOS at levels comparable to normal dogs. Analysis of the peripheral blood CD3+ T-cells isolated from dogs showed a significant up-regulation of ICOS expression 3 days but not 6–7 days before the diagnosis of chronic GVHD. Pharmacokinetic studies of 123I-labled anti-canine ICOS showed normal blood clearance profiles. These studies demonstrated that an antagonistic anti-canine ICOS mAb may have application in the prevention or treatment of GVHD in an outbred animal model shown to reliably translate novel hematopoietic cell transplantation therapies to the clinic. Disclosures: No relevant conflicts of interest to declare.

Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Immunotherapy ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. 599-621
Author(s):  
Jian-Ming Li ◽  
Cynthia R Giver ◽  
Ying Lu ◽  
Mohammad S Hossain ◽  
Mojtaba Akhtari ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Routine methods to maximize the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic stem cell transplantation (HSCT) without the detrimental effects of graft-versus-host disease (GvHD) are lacking. Depletion or inhibition of alloreactive T cells is partially effective in preventing GvHD, but usually leads to decreased GvL activity. The current model for the pathophysiology of acute GvHD describes a series of immune pathways that lead to activation of donor T cells and inflammatory cytokines responsible for tissue damage in acute GvHD. This model does not account for how allotransplant can lead to GvL effects without GvHD, or how the initial activation of donor immune cells may lead to counter-regulatory effects that limit GvHD. In this review, we will summarize new findings that support a more complex model for the initiation of GvHD and GvL activities in allogeneic HSCT, and discuss the potential of novel strategies to enhance GvL activity of the transplant.

scholarly journals Low telomerase activity in CD4+ regulatory T cells in patients with severe chronic GVHD after hematopoietic stem cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 5021-5030 ◽  
Author(s):  
Yutaka Kawano ◽  
Haesook T. Kim ◽  
Ken-ichi Matsuoka ◽  
Gregory Bascug ◽  
Sean McDonough ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Telomere Length ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Telomerase Activity ◽  
Hematopoietic Stem

Abstract CD4+CD25+Foxp3+ regulatory T cells (Treg) play an important role in the control of chronic graft-versus-host disease (cGVHD). In this study, we examined telomere length and telomerase activity of Treg and conventional CD4+ T cells (Tcon) in 61 patients who survived more than 2 years after allogeneic hematopoietic stem cell transplantation. Cell proliferation and expression of Bcl-2 were also measured in each subset. Treg telomere length was shorter and Treg telomerase activity was increased compared with Tcon (P < .0001). After transplantation, Treg were also more highly proliferative than Tcon (P < .0001). Treg number, telomerase activity, and expression of Bcl-2 were each inversely associated with severity of cGVHD. These data indicate that activation of telomerase is not sufficient to prevent telomere shortening in highly proliferative Treg. However, telomerase activation is associated with increased Bcl-2 expression and higher Treg numbers in patients with no or mild cGVHD. In contrast, patients with moderate or severe cGVHD have fewer Treg with lower levels of telomerase activity and Bcl-2 expression. These results suggest that failure to activate Treg telomerase may restrict proliferative capacity and increase apoptotic susceptibility, resulting in the loss of peripheral tolerance and the development of cGVHD.

Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3162-3164 ◽  
Author(s):  
Ai Kotani ◽  
Takayuki Ishikawa ◽  
Yumi Matsumura ◽  
Tatsuo Ichinohe ◽  
Hitoshi Ohno ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Therapeutic Response ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract There is no reliable laboratory indicator of the onset of chronic graft-versus-host disease (cGVHD). This study looks at whether the expression of OX40, a member of the tumor necrosis factor receptor family, is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplantation. Peripheral blood mononuclear cells from 22 patients after day 100 were subjected to multicolor flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+T cells were significantly higher in patients with cGVHD than those without (P &lt; .0001 and P = .001, respectively). Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and closely correlated with the therapeutic response. The expression of CD25, CD69, and HLA-DR was partially detectable on OX40+ T cells. These results indicate that serial measurement of OX40+ T cells is useful for predicting the onset as well as the therapeutic response of cGVHD and raise a possibility that the OX40/gp34 system is involved in the pathogenesis of cGVHD.

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