scholarly journals Central Roles of OX40L–OX40 Interaction in the Induction and Progression of Human T Cell–Driven Acute Graft-versus-Host Disease

2019 ◽  
Vol 3 (3) ◽  
pp. 110-120 ◽  
Author(s):  
Trivendra Tripathi ◽  
Wenjie Yin ◽  
Yaming Xue ◽  
Sandra Zurawski ◽  
Haruyuki Fujita ◽  
...  
Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
Author(s):  
PY Dietrich ◽  
A Caignard ◽  
A Lim ◽  
V Chung ◽  
JL Pico ◽  
...  

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.


Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3440-3448 ◽  
Author(s):  
G Hoffmann-Fezer ◽  
C Gall ◽  
U Zengerle ◽  
B Kranz ◽  
S Thierfelder

Abstract Surprisingly little graft-versus-host disease (GVHD) has been observed in severe combined immunodeficient (SCID) mice injected intraperitoneally (IP) with human blood lymphocytes (hu-PBL-SCID), which raised the question as to whether GVHD in such a distant species is sporadic or suppressed because of immunologic reasons. After screening for blood T-cell chimerism, we hereby describe generalized lethal xenogeneic human GVHD in unconditioned SCID chimeras, which resembles GVHD in SCID mice injected with allogeneic lymphocytes. We adapted an immunocytochemical slide method for minute cell numbers, which allowed us to follow, by multimarker phenotyping of weekly mouse- tail bleeds, the chimeric status of 100 hu-PBL-SCID injected with 10(7) or 10(8) hu-PBL of Epstein-Barr virus- (EBV-) donors. More than half of the mice showed no or less than 2% T cells. However, 13% to 21% developed substantial blood T-lymphocyte chimerism (10% to 80% human CD+ cells) and high mortality. Immunohistology showed more human CD8+ than CD4+ T cells in the splenic white pulp. The cells developed HLA-DR activation markers and infiltrated the red pulp where human B cells also appeared. Expression of activation and proliferation markers increased within 5 to 6 weeks. Many human CD3+ cells were also found in the portal triads of the liver and in the lung, pancreas, and kidney. The thymus also became heavily infiltrated. The intestines and skin of hu-PBL-SCID were less infiltrated by donor cells than in SCID with allogeneic GVHD. The tongue contained almost no human T cells. Our data show that a relatively low overall incidence of human xenogeneic GVHD, even when high numbers of human PBL are injected, is the consequence of a dichotomy between mice with no or transient T-cell chimerism and a minority of mice with high-blood T-lymphocyte chimerism and GVHD mortality.


Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2815-2820 ◽  
Author(s):  
PY Dietrich ◽  
A Caignard ◽  
A Lim ◽  
V Chung ◽  
JL Pico ◽  
...  

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.


2020 ◽  
Vol 140 (7) ◽  
pp. 1455-1459.e6
Author(s):  
Lukas Freund ◽  
Stephanie Oehrl ◽  
Galina Gräbe ◽  
Patrick Gholam ◽  
Thomas Plum ◽  
...  

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3479-3482 ◽  
Author(s):  
Joseph H. Antin ◽  
Daniel Weisdorf ◽  
Donna Neuberg ◽  
Roberta Nicklow ◽  
Shawn Clouthier ◽  
...  

Acute graft-versus-host disease (GVHD) is thought to derive from direct T-cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as interleukin-1 (IL-1), tumor necrosis factor α, and interferon γ may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T-cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double-blind, placebo-controlled randomized trial of recombinant human IL-1 receptor antagonist (IL-1Ra) in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day −4 to day +10. Randomization was stratified according to GVHD risk. The 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P = .88). There was no difference in hematologic recovery, transplantation-related toxicity, event-free survival, or overall survival. We conclude that blockade of IL-1 using IL-1Ra during conditioning and 10 days immediately after transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.


2015 ◽  
Vol 13 (2) ◽  
pp. 1395-1403 ◽  
Author(s):  
KAI ZHAO ◽  
SUHONG RUAN ◽  
LINGLING YIN ◽  
DONGMEI ZHAO ◽  
CHONG CHEN ◽  
...  

1991 ◽  
Vol 34 (2) ◽  
pp. 97-102 ◽  
Author(s):  
Dietrich W. Beelen ◽  
Hans Grosse-Wilde ◽  
Ursula Ryschka ◽  
Klaus Quabeck ◽  
Herbert G. Sayer ◽  
...  

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