scholarly journals In Vivo Maturation of Allo-Specific CD8 CTL and Prevention of Lupus-like Graft-versus-Host Disease Is Critically Dependent on T Cell Signaling through the TNF p75 Receptor But Not the TNF p55 Receptor

2013 ◽  
Vol 190 (9) ◽  
pp. 4562-4572 ◽  
Author(s):  
Kateryna Soloviova ◽  
Maksym Puliaiev ◽  
Mark Haas ◽  
Charles S. Via
Keyword(s):  
T Cell ◽  
Cell Signaling ◽  
Graft Versus Host Disease ◽  
T Cell Signaling ◽  
Host Disease ◽  
Graft Versus Host ◽  
P75 Receptor

scholarly journals In vivo T-cell clonal amplification at time of acute graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
Author(s):  
PY Dietrich ◽  
A Caignard ◽  
A Lim ◽  
V Chung ◽  
JL Pico ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Donor Blood ◽  
Host Disease ◽  
Graft Versus Host ◽  
Junctional Region ◽  
Run Off ◽  
Pcr Products ◽  
Acute Graft

In a series of patients transplanted with HLA-matched allogeneic bone marrow grafts (alloBMT), we previously showed that a few T-cell receptor (TCR) V alpha and V beta gene segment transcripts were overexpressed in skin compared with blood at the time of acute graft- versus-host disease (aGVHD). Here, in one selected patient with overexpressed V beta 16 and V alpha 11 transcripts in skin, we analyzed the junctional variability of these transcripts in donor blood, patient blood, and skin collected at aGVHD onset. A unique junctional region sequence accounted for 81% of in frame V beta 16 transcripts (13 of 16) in skin and 59% (13 of 22) in patient blood. Similarly, two recurrent junctional region sequences were found in skin V alpha 11 transcripts, one accounting for 66% (21 of 32) and the other for 16% (5 of 32). These recurrences were also found in patient blood (36% and 15% of V alpha 11 transcripts, respectively). To extend our analysis, a polymerase chain reaction (PCR)-based method was used to precisely determine TCR beta transcript length in run-off reactions using uncloned bulk cDNA samples. All V beta-C beta PCR products analyzed in donor blood, as well as the majority of those analyzed in patient blood, included transcripts with highly diverse junctional region sizes. As expected from the sequence data, most V beta 16-C beta PCR products in skin and patient blood were of the same size (ie, same junctional region). In addition, V beta 3, V beta 5, and V beta 17 transcripts in skin were shown to display highly restricted size variability. The clonality of the V beta 16-C beta and V beta 17-C beta transcripts was further supported by the results of run-off reactions using 13 J beta specific primers. We have identified several recurrent TCR transcripts in skin, some of them also present in patient blood. These data support the view that several T-cell subpopulations are clonally expanded in vivo at the time of aGVHD onset in this case of related HLA-matched alloBMT.

scholarly journals In vivo T-cell clonal amplification at time of acute graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
Author(s):  
PY Dietrich ◽  
A Caignard ◽  
A Lim ◽  
V Chung ◽  
JL Pico ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Donor Blood ◽  
Host Disease ◽  
Graft Versus Host ◽  
Junctional Region ◽  
Run Off ◽  
Pcr Products ◽  
Acute Graft

Abstract In a series of patients transplanted with HLA-matched allogeneic bone marrow grafts (alloBMT), we previously showed that a few T-cell receptor (TCR) V alpha and V beta gene segment transcripts were overexpressed in skin compared with blood at the time of acute graft- versus-host disease (aGVHD). Here, in one selected patient with overexpressed V beta 16 and V alpha 11 transcripts in skin, we analyzed the junctional variability of these transcripts in donor blood, patient blood, and skin collected at aGVHD onset. A unique junctional region sequence accounted for 81% of in frame V beta 16 transcripts (13 of 16) in skin and 59% (13 of 22) in patient blood. Similarly, two recurrent junctional region sequences were found in skin V alpha 11 transcripts, one accounting for 66% (21 of 32) and the other for 16% (5 of 32). These recurrences were also found in patient blood (36% and 15% of V alpha 11 transcripts, respectively). To extend our analysis, a polymerase chain reaction (PCR)-based method was used to precisely determine TCR beta transcript length in run-off reactions using uncloned bulk cDNA samples. All V beta-C beta PCR products analyzed in donor blood, as well as the majority of those analyzed in patient blood, included transcripts with highly diverse junctional region sizes. As expected from the sequence data, most V beta 16-C beta PCR products in skin and patient blood were of the same size (ie, same junctional region). In addition, V beta 3, V beta 5, and V beta 17 transcripts in skin were shown to display highly restricted size variability. The clonality of the V beta 16-C beta and V beta 17-C beta transcripts was further supported by the results of run-off reactions using 13 J beta specific primers. We have identified several recurrent TCR transcripts in skin, some of them also present in patient blood. These data support the view that several T-cell subpopulations are clonally expanded in vivo at the time of aGVHD onset in this case of related HLA-matched alloBMT.

scholarly journals Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester: elimination of graft-versus-host disease without detrimental effects on engraftment

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 798-805 ◽  
Author(s):  
BR Blazar ◽  
DL Thiele ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Methyl Ester ◽  
Graft Versus Host Disease ◽  
Host Cells ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host

Abstract Incubation of murine bone marrow and splenocytes with the dipeptide methyl ester, L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), which results in the selective depletion of cytotoxic T cells and their precursors, natural killer cells, and monocytes, completely protected 30 recipients of fully allogeneic donor grafts from lethal graft-versus- host disease (GVHD). These results were comparable with those obtained in 30 recipients of anti-Thy 1.2 plus complement (C')-treated donor marrow. However, in contrast to antibody- and C'-dependent T-cell depletion, which reduces the level of donor cell engraftment in our model system, we did not observe such effects using Leu-Leu-OMe marrow pretreatment. As compared with the 24 H-2 typed recipients of anti-Thy 1.2 + C'-treated donor grafts, the 29 H-2 typed recipients of Leu-Leu- OMe-treated donor grafts had significantly (P less than .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P less than .001) lower percentages of host cells (mean = 6% v 15%) posttransplantation. In vitro limiting dilution assay (LDA) was performed to assess the comparative efficacy of cytolytic T-lymphocyte (CTL) precursor depletion by Leu-Leu-OMe or anti-Thy 1.2 + C' pretreatment. We observed greater levels of CTL precursor depletion in Leu-Leu-OMe treated as compared with anti-Thy 1.2 + C'-treated bone marrow plus spleen cells (BMS) obtained from nontransplanted mice. This suggests that the in vivo results cannot simply be attributed to a less efficacious functional inactivation of cytolytic T-cell precursors by Leu-Leu-OMe treatment as compared with anti-Thy 1.2 + C' treatment. Immunoreconstitution was similar in recipients of Leu-Leu-OMe-treated grafts and anti-Thy 1.2 + C'-treated grafts 100 days posttransplant. In our opinion, Leu-Leu-OMe marrow pretreatment deserves further investigation as a methodology to achieve GVHD prevention without significantly reducing the propensity toward host cell repopulation.

Host γd T cells Exacerbate Experimental Acute Graft-Versus-Host Disease through Activation of Host Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3045-3045
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Chen Liu ◽  
D. Keith Bishop ◽  
James L.M. Ferrara
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Serum Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Full Intensity

Abstract Large numbers of T cells bearing γd T cell receptors are present in graft-versus-host disease (GVHD) target tissues. We investigated the potential role of host γd T cells during acute GVHD in a well-characterized GVHD model following full intensity conditioning (11 Gy TBI). BM and spleen T cells from BALB/c (H2d) donors were transplanted into wild type (wt) B6, aß T cell deficient B6 (aß −/−) or γd T cell deficient B6 (γd −/−) hosts. γd −/− hosts demonstrated significantly better day 35 survival (85%) than wt (40%) or aß−/− hosts (18%) (P<0.05). Reconstitution of γd −/− B6 hosts with B6 type γd T cells 24 hr prior to BMT restored lethal GVHD (50 % day 35 survival). In vivo, γd −/− B6 hosts demonstrated at least a five fold reduction in donor T cell expansion and cytokine production. In vitro, T cells proliferated less when co-cultured with allogeneic γd −/− dendritic cells (DCs) than with wt DCs (40,127 ± 1634 vs. 72,503 ± 1296, P<0.05). BM-derived DCs cultured with γd T cells caused greater proliferation of allogeneic T cells than DCs cultured with aß T cells (15.1 ± 21 x 104 vs. 5.1 ± 1.2 x 104, P<0.05). We next tested the effect of γd T cells on host DCs in vivo using a model system in which only the DCs injected prior to BMT expressed the alloantigen that stimulated the GVHD reaction. MHC Class II −/− B6 mice that had been depleted of γd T cells were given 11 Gy TBI and injected one day prior to BMT with B6 DCs that had been co-cultured either with γd T cells or with medium. On day 0 both groups of recipient mice were injected with BM plus splenic T cells from allogeneic bm12 donors. On day +5, CD4+ donor T cells expanded four times more in recipients of DCs co-cultured with γd T cells than in recipients of control DCs and serum levels of TNF-a were significantly higher (36.7 + 6.8 vs. 21.3 + 3.7 pg/ml, P<0.05). Together these data demonstrate that γd T cells amplify the stimulatory function of host DCs and increase the severity of GVHD, suggesting that a new therapeutic target for the prevention of the major BMT toxicity.

Donor Dual TCR T Cells Preferentially Expand and Mediate Pathologic Alloreactivity in Acute Graft Versus Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1972-1972
Author(s):  
Gerald P. Morris ◽  
Geoffrey L Uy ◽  
David L Donermeyer ◽  
Paul M Allen ◽  
John F. DiPersio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Thymic Selection ◽  
Cell Repertoire ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 1972 The nature of the T cell repertoire mediating pathologic in vivo alloreactivity is an important question for understanding the development of acute graft-versus-host disease (aGvHD) following clinical allogeneic transplantation. We have previously demonstrated that the small proportion of T cells that naturally express 2 T cell receptors (TCR) as a consequence of incomplete TCRa allelic exclusion during thymic development contribute disproportionately to the alloreactive T cell repertoire, both in vitro and in vivo in a mouse model of graft versus host disease (GvHD) (J. Immunol., 182:6639, 2009). Here, we extend these findings to human biology, examining dual TCR T cells from healthy volunteer donors (n = 12) and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) (n = 19). Peripheral blood was collected at day 30 post-HSCT or at the time of presentation with symptomatic acute GvHD. Dual TCR T cells were measured in peripheral blood by pair-wise staining with 3 commercially-available and 2 novel TCRa mAbs. Dual TCR T cells were consistently and significantly expanded in patients with symptomatic aGvHD, representing 5.3±3.8 % of peripheral T cells, compared to 1.7±0.8 % of T cells in healthy controls (p < 0.005) (Figure 1). There was no correlation between dual TCR T cell frequency and GvHD severity. Furthermore, sequential analysis of peripheral blood in 2 patients demonstrated expansion of dual TCR T cells concurrent with the development of aGvHD (Figure 2). Dual TCR T cells from patients with symptomatic aGvHD demonstrated increased expression of CD69 as compared to T cells expressing a single TCR, indicative of preferential activation of dual TCR T cells during aGvHD. Similarly, dual TCR T cells isolated from patients with symptomatic aGvHD demonstrate increased production of IFN-g ex vivo, indicative of the ability to mediate pathogenic alloreactive responses. Dual TCR T cell clones isolated from healthy donors and patients post-HSCT by single cell FACS sorting demonstrate alloreactive responses against a range of allogeneic cell lines in vitro. We propose that the increased alloreactivity of dual TCR T cells results from the less stringent thymic selection for secondary TCR, and thus provides a link between thymic selection, the TCR repertoire, and alloreactivity. These findings may lead to simple ways of phenotypically identifying specific T cells predisposed to inducing aGvHD for subsequent examination of T cell repertoires and functional studies. Furthermore, these data suggest that dual TCR T cells represent a potential predictive biomarker for aGvHD and a potential target for selective T cell depletion in HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IN VIVO REACTIVITY OF T CELL CLONES ISOLATED FROM MICE WITH SYNGENEIC GRAFT-VERSUS-HOST DISEASE

1995 ◽  
Vol 60 (2) ◽  
pp. 171-178 ◽  
Author(s):  
J SCOTT BRYSON ◽  
HELENE LAKE-BULLOCK ◽  
DAVID L. PFLUGH ◽  
C DARRELL JENNINGS ◽  
P MICHAEL STUART ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

Dendritic cell–activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3970-3978 ◽  
Author(s):  
Yi Zhang ◽  
Gerard Joe ◽  
Jiang Zhu ◽  
Richard Carroll ◽  
Bruce Levine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Graft Versus Host Disease ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Antitumor Effects ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft versus host disease (GVHD) is triggered by host antigen-presenting cells (APCs) that activate donor T cells to proliferate and differentiate, but which APC-activated donor T-cell subsets mediate GVHD versus beneficial antitumor effects is not known. Using a CD8+ T cell–dependent mouse model of human GVHD, we found that host dendritic cell (DC)–induced CD44hiCD8+ effector/memory T cells were functionally defective in inducing GVHD, whereas CD44loCD8+ naive phenotype T cells were extremely potent GVHD inducers. Depletion of CD44loCD8+ T cells from host DC-stimulated T cells before transplantation prevented GVHD without impairing their antitumor activity in vivo. Compared with CD44loCD8+ T cells, CD44hiCD8+ T cells expressed high levels of Fas and were efficiently deleted in vivo following transplantation. These results suggest that ex vivo allogeneic DC stimulation of donor CD8+ T cells may be useful for the prevention of GVHD and for optimizing antitumor therapies in vivo.

Inhibition of Graft-Versus-Host Disease (GVHD) by Histone Deacetylase Inhibitor (HDAC) SAHA Leads to Downregulation of STAT1 Activation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1311-1311
Author(s):  
Corinna Leng ◽  
Cuiling Li ◽  
Judy Ziegler ◽  
Anna Lokshin ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Histone Deacetylase ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Ifn Γ

Abstract Histone deacetylase (HDAC) inhibitors have been shown to reduce development of graft versus host disease [GVHD] following allogeneic bone marrow transplantation [BMT]. Administration of the HDAC inhibitor suberonylanilide hydroxamic acid [SAHA] resulted in a significantly reduced GVHD-dependent mortality following fully MHC-mismatched allogeneic BMT. Median Survival Time (MST) for vehicle and SAHA-treated mice were 7.5 days and 38 days respectively. However, SAHA treatment did not affect T cell activation nor T cell expansion in vitro and in vivo as determined by MLR assays, phenotypic analysis of donor T cells with regard to expression of the CD25 activation antigen and calculation of donor CD4+ and CD8+ T cell numbers on days +3 and +6 post-BMT. Thus, SAHA treatment was not able to inhibit the strong upregulation of CD25 antigen on CD8+ T cells observed during induction of GVHD on days +3 and +6 post-BMT. We therefore focused on the effects of SAHA treatment on efferent immune effects including cytokine secretion and intracellular signaling events in vitro and in vivo following GVHD induction. SAHA treatment broadly inhibited lipopolysaccharide [LPS] and allo-antigen-induced cytokine/chemokine secretion in vitro like MIP-1-α, IP-10, IFN-γ, TNF-α and IL-6 and led also to a significant decrease in IFN-γ and TNF-α levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and allo-activation in vitro. Furthermore, analysis of liver tissue and spleens from SAHA-treated animals with GVHD showed a significant decrease in phosphorylated STAT1. In contrast SAHA treatment had only moderate effects on p38 or ERK1,2 Mitogen-activated Protein Kinase (MAPK) pathway underscoring the relevance of the inhibition of the STAT1 pathway. In conclusion, GVHD is associated with a strong induction of phosphorylation of STAT1 in the liver and spleen and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of pSTAT1 and modulation of the inflammatory cytokine milieu during the efferent immune response.

Prevention of Acute Graft-Versus-Host Disease Despite Compensatory Function of Lymphoid Organs In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 582-582 ◽  
Author(s):  
Andreas Beilhack ◽  
Stephan Schulz ◽  
Jeanette Baker ◽  
Georg F. Beilhack ◽  
Ryosei Nishimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Time Course ◽  
Lymphoid Organs ◽  
Host Disease ◽  
Graft Versus Host ◽  
Deficient Mice ◽  
Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) results from alloreactive donor derived T cells attacking targets in the gastrointestinal tract, liver and skin. We observed the initiation and rapid kinetics of aGVHD in a murine model [FVB/N (H-2q) into irradiated Balb/c (H-2d)] using in vivo bioluminescence imaging. The transition from the initiation to the effector phase of aGVHD (day 3–4) was characterized by rapid T cell proliferation and upregulation of gut homing receptors alpha4beta7, alphaEbeta7 and CCR9 on alloreactive T cells in Peyer’s patches (PP), mesenteric lymph nodes (LN) and spleen, but not peripheral LNs. Therefore we asked whether the lack of specific lymphoid priming sites would lead to decreased alloreactive T cell infiltration in the gut compared to the liver and skin. Using PP deficient mice, we observed that mesenteric LN and spleen compensate for the lack of PP as alloreactive priming sites. Transplantation of PP and LN deficient mice (TNFalpha-/-) showed that the spleen alone was sufficient to cause the complete profile of aGVHD with a time course similar to that of wildtype mice. Splenectomized mice with intact secondary lymphoid organs also developed aGVHD. Strikingly, treatment of splenectomized recipients with blocking antibodies against the lymphoid homing receptors L-selectin and MAdCAM-1 prevented GVHD with 100% survival (&gt;120 d, p&lt;0.0001). Our study shows that multiple priming sites are involved in GVHD initiation, the spleen compensating for the lack of PP and mesenteric LN, and vice versa. In contrast, splenectomy and antibody blocking resulted in a clear survival benefit for all recipients.

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