scholarly journals Chronic Graft-Versus-Host Disease Immunoprofiling Reveals T Cell Clonal Dynamics That Correlate with Disease Activity: A Novel Molecular "Biomarker"?

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3811-3811
Author(s):  
Anna Vardi ◽  
Elisavet Vlachonikola ◽  
Dimitra Gkouvelou ◽  
Evdoxia Koravou ◽  
Electra Sofou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Disease Activity ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Additional Patient ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

Abstract Chronic graft-versus-host disease (cGVHD) is the main cause of morbidity and transplant-related mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT), however effective treatment options are limited. Lack of objective surrogates (biomarkers) for treatment response has hindered progress in this respect. T cells are considered the major effectors of cGVHD, yet the respective repertoires are insufficiently charted. Here, we investigated the dynamic architecture of T-cell repertoires in cGVHD by exploiting next-generation sequencing (NGS), aiming to uncover immunogenetic signatures linked with cGHVD occurrence and response to treatment. We analyzed 53 blood samples from 15 patients with hematological malignancies who underwent alloHSCT, with an intended bias towards patients who developed cGVHD (n=12). The remaining 3 patients had no cGVHD (control group). Patients with cGVHD were analyzed at cGVHD onset and/or prior to a new line of treatment (n=17 samples) as well as at clinically relevant timepoints following treatment: (i) partial response (PR, n=8), (ii) complete response (CR, n=3), (iii) stable disease (SD, n=18), (iv) progression (PD, n=1). Treatment modalities involved corticosteroids, mycophenolate myfetil, extracorporeal phototherapy, ruxolitinib and ibrutinib. Patients with no cGVHD were analyzed at 3 months (+3mo) and 6 months (+6mo) post-alloHSCT (n=6 samples). Starting material was PB mononuclear cells. TRBV-TRBD-TRBJ gene rearrangements were RT-PCR amplified and subjected to paired-end NGS and detailed bioinformatics analysis. Only productive TRBV-TRBD-TRBJ rearrangements were evaluated (n= 13,059,730, 89.9% of filtered-in sequences, median 219,063/sample). For repertoire characterization, clonotypes (i.e., TRB rearrangements with identical TRBV gene usage and amino acid complementarity-determining region 3 sequence) were considered (median 9,725 distinct clonotypes/sample). The 10 most frequent clonotypes/sample were defined as "major". To purge T cell clones expanded secondary to viruses common in the alloHSCT setting, we compared all major clonotypes against the GenBank TRB sequence database (n=18,402), as well as an extensive TR repertoire dataset from a previous study by our group, profiling tri-virus-specific (CMV, EBV, BK) T cell products generated from immunocompetent donors (n=947,298). Overall, we identified 289 unique major clonotypes; 38 were excluded due to match within the tri-VST database (no match within GenBank). All cases with cGVHD displayed significant clonal T cell expansions both pre- and post-treatment (overall median cumulative frequency of the 6 most expanded T cell clonotypes/sample 32.4%). However, clonality tended to decrease in PR samples compared to pre-treatment (19.8% vs 33.9%, respectively), although not reaching statistical significance possibly due to small sample size (p=0.06). Patients with no cGVHD, on the other hand, consistently displayed a clonality decrease overtime (31.8% at +3mo vs 18.4% at +6mo, p=0.02). Importantly, patients with no GVHD displayed TR repertoire reconstitution with few major T cell clones of the +3mo timepoint persisting at +6mo (median 20%). In clear contrast, cGVHD T cell repertoires were dominated by clones which persisted overtime (median 60%). In fact, repertoire persistence was most evident in SD (median 66.7%) and significantly lower in PR and CR (33.3% and 10.0%, respectively, p<0.05), suggesting that the persisting T cell clones are implicated in cGVHD pathogenesis. Notably, repertoire comparisons across patients in our cohort revealed 6 "public" clonotypes [5 clonotypes shared among a single pair of patients (Pt1 and Pt2) and 1 clonotype shared among the same pair plus an additional patient, Pt3], suggesting the existence of a common antigenic trigger. In conclusion, NGS immunoprofiling in cGVHD reveals expanded T cell clones with clonal dynamics that correlate with clinical response, indicating a causal relationship to cGVHD pathogenesis. Identification and longitudinal tracking of T cell clones associated with cGHVD could serve as a molecular surrogate marker for disease activity, with evident benefits for cGVHD monitoring and evaluation of response to various treatments. Disclosures Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Chatzidimitriou: Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

GRAFT-VERSUS-HOST-DISEASE-ASSOCIATED THYMIC DAMAGE RESULTS IN THE APPEARANCE OF T CELL CLONES WITH ANTI-HOST REACTIVITY1

2000 ◽  
Vol 69 (3) ◽  
pp. 446-450 ◽  
Author(s):  
Marcel R. M. van den Brink ◽  
Ellen Moore ◽  
James L. M. Ferrara ◽  
Steven J. Burakoff
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

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

scholarly journals HLA-target antigens and T-cell receptor diversity of activated T cells invading the skin during acute graft-versus-host disease

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2345-2353 ◽  
Author(s):  
J Gaschet ◽  
MA Trevino ◽  
M Cherel ◽  
R Vivien ◽  
A Garcia-Sahuquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

To study the repertoire and specificity of T lymphocytes infiltrating skin lesions during graft-versus-host disease (GVHD), we performed an exhaustive molecular and functional analysis of 146 T-cell clones derived from the skin of three patients undergoing an acute GVHD after allogeneic bone marrow transplantation (BMT) from HLA-mismatched related donors. Analysis of T-cell receptor (TCR) rearrangement and TCR chain junctional sequences demonstrated the presence of 11 distinct clones among the 64 derived from patient UPN1, six among the 58 derived from patient UPN2, and seven among the 24 derived from patient UPN3. Three of the 11 T-cell clones from patient UPN1, and all clones from patients UPN2 and UPN3 reacted with mismatched HLA alleles between the bone-marrow donor and recipient. Moreover, both HLA class I (HLA-A2 and -B27) and class II (HLA DP101, DP401, DP1301, DQ8, and DR402) molecules were recognized during this early antihost response. Finally, both TCR alpha and beta chains turned out to be extremely diverse, even within populations of clones derived from the same patient and directed against the same HLA allele. Taken together, these results indicate that any HLA mismatch is potentially targeted during early GVHD, and that the T-cell response at the onset of GVHD is both oligoclonal and highly diversified.

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

Establishment of T-cell clones recognizing difference in H-2K antigen and inducing graft-versus-host disease

1985 ◽  
Vol 94 (2) ◽  
pp. 454-465 ◽  
Author(s):  
H. Watanabe ◽  
M. Fujiwara ◽  
T. Nishiyama ◽  
M. Ito ◽  
T. Mashiko ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

Inhibition Of The Immunoproteasome Subunit LMP7 Decreases Alloresponses In Both MHC-Mismatched and miHA-Disparate Murine Models Of Graft Versus Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4472-4472
Author(s):  
Jennifer Matos ◽  
Zheng Yang ◽  
Eugenia Dziopa ◽  
Leah Dziopa ◽  
Christopher J. Kirk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Host Cells ◽  
Mhc I ◽  
Host Disease ◽  
Graft Versus Host ◽  
Drug Regimens

Background Proteasome inhibition has been studied and used as a therapeutic target in the treatment of autoimmune disorders and multiple myeloma. Immune system cells, especially antigen-presenting cells, express a higher basal level of immunoproteasomes, which are used to generate peptides that can be processed to fit in the groove of MHC class I molecules. ONX 0914 is a selective inhibitor of the immmunoproteasome that blocks LMP7-specific presentation of MHC-I restricted antigens, whereas PR-825 is a specific inhibitor of the b5 catalytic subunit generated by the constitutive proteasome. In previous work, we found that ONX 0914 administration early after transplantation significantly improved the survival of recipient mice in an MHC-matched minor histocompatibility antigen (miHA)-disparate (B10.BR -> CBA, lethally irradiated) murine model of graft-versus-host disease (GVHD). To further elucidate the mechanism of action, we compared alloreactive responses via IFN-g production in mixed lymphocyte reactions (MLR) in which stimulator cells or responder T cells were pretreated with either ONX 0914 or PR-825. MLR were conducted for the B10.BR anti-C56BL/6y (B6) MHC-mismatched, the CD8+ T cell-mediated B10.BR anti-CBA, and the CD4+ T cell-mediated B6 anti-BALB.B MHC-matched/ miHA-disparate strain combinations. Methods Stimulator splenocytes were treated for one hour with ONX 0914 (300 nM) or PR-825 (125 nM) before or immediately after exposure to irradiation (30 Gy) prior to initiation of the MLR. In addition, to try to optimize putative in vivo drug regimens, we determined the timing of release/degradation of antigenic peptides presented in the context of MHC-I. To this end, the MC57G fibrosarcoma cell line was transiently transfected with a GFP tagged SIINFEKL plasmid, cells were treated with different drug regimens and exposure times of ONX 0914 or PR-825, and monitored over 48 hours for surface expression of MHC-I presented SIINFEKL peptide using flow cytometry. Results ELISpot assays showed a statistically significant decrease in the number of IFN-g producing cells when stimulators (B6 splenocytes) were pretreated with ONX 0914 compared to pretreated responder (B10.BR) cells (60.21% vs. 1.75% respectively, p< 0.01). In the miHA disparate combinations, the percentage decrease in IFN-g+ spots was ∼30% when stimulators were treated with ONX 0914, whereas only a ∼15% decrease was observed with PR-825 pretreatment. Furthermore, IFN-g production was not dependent upon the timing of exposure to irradiation, as ELISpot counts were equally decreased when drug pretreatments were performed before irradiation or just after exposure. Antigenic peptide presentation was maximally decreased in transfected MC57G cells 48 h after treatment (i.e., SIINFEKL % in GFP+ MC57G cells treated with DMSO was equal to 83% vs. 76% when cells were exposed to ONX 0914 [300 nM, for 24 h]. This result suggests that for in vivo application, pretreatment of recipient mice with ONX 0914 to decrease miHA presentation by host cells (24-72 hours prior to bone marrow transplantation) may provide further amelioration of GVHD development. Conclusion Taken together, these data suggest that downregulation of LMP7-mediated presentation of MHC-I restricted antigens by host cells likely modulated stimulation and IFN-g production of donor T cells in vivo, rather than acting on effector cells directly, and accounted in part for the improved survival rate experienced by recipient mice treated with ONX 0914. Disclosures: Matos: Onyx Pharmaceuticals: Research Funding. Dziopa:Onyx Pharmaceuticals: Research Funding. Kirk:Onyx Pharmaceuticals: Employment. Korngold:Onyx Pharmaceuticals: Research Funding. Zilberberg:Onyx Pharmaceuticals: Research Funding.

APG101 - a Novel Inhibitor of CD95/CD95L Signaling Prevents Graft-Versus-Host Disease without Disabling T Cell Effector Function and Anti-Tumor Activity,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4019-4019
Author(s):  
Gudrun Strauss ◽  
Natalie Hartmann ◽  
Michael Kluge ◽  
Harald Fricke ◽  
Klaus-Michael Debatin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Cell Function ◽  
Therapeutic Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tumor Cytotoxicity ◽  
Cell Effector

Abstract Abstract 4019 Allogeneic bone marrow transplantation (BMT) is a curative treatment modality for haematological malignancies since mature allogeneic T cells in the transplant efficiently eliminate residual tumor cells (graft-versus-tumor (GVT) effect). However, these donor T cells are also responsible for the induction of graft-versus-host disease (GVHD) by attacking recipient tissue leading to significant morbidity and mortality. Interfering with T cell effector mechanisms responsible for GVHD-induction without preventing T cell functions towards third-party or opportunistic pathogens and while maintaining anti-tumor cytotoxicity might lead to new treatment strategies after allogeneic BMT. The CD95/CD95L system significantly contributes to GVHD-associated tissue damage and intervention into this signaling pathway might therefore inhibit GVHD-development without disturbing the GVT-effect. APG101 is a human soluble fusion protein consisting of the extracellular domain of CD95 and the Fc portion of IgG blocking the interaction of CD95L with its cognate receptor. We tested the effect of APG101 on T cell function, GVHD development and anti-tumor cytotoxicity in an allogeneic parent into F1 (C57BL/6 (B6) (H-2b) into B6D2F1 (H-2bxd)) BMT model with a mismatch in HLA-Class I and II molecules. In vitro, APG101 efficiently inhibited CD95L-mediated apoptosis of primary naïve mouse CD4+ and CD8+ T cells but did not interfere with their proliferative or cytotoxic capacity. To test APG101 as a therapeutic agent in BMT we induced acute GVHD in lethally irradiated B6D2F1 mice by transplantation of B6-derived BM together with allogeneic spleen cells. APG101 treatment was conducted intraperitoneally twice a week until the end of the experiment, starting either one day before BMT (= prophylactic treatment) or starting six or thirteen days after BMT (= therapeutic treatment). Prophylactic and early (day 6), but not late therapeutic treatment (day 13), effectively protected recipients from clinical GVHD and significantly improved survival. Although APG101 efficiently prevented GVHD-induction, homing and proliferation of allogeneic T cells into lymphoid organs and GVHD-target organs was unaltered compared to non-treated animals. Since CD95L is also known as a reverse signaling co-stimulator in T cell activation, APG101 might interfere with T cell function in vivo. However, no differences in phenotype, proliferation or cytokine expression of transplanted allogeneic T cells was observed in APG101-treated mice compared to non-treated mice. Most importantly, the GVT effect was preserved in APG101-treated mice. Anti-tumor cytotoxicity of transplanted allogeneic T cells was not abrogated by APG101 injection independent whether the murine mastocytoma cell line P815 or Bcr-Abl transduced primary B-ALL cells were injected. In summary, our findings convincingly show that early APG101 treatment is a promising approach to prevent GVHD without abrogating T cell effector functions and while preserving the GvT effect after allogeneic BMT. Disclosures: Strauss: Apogenix: Research Funding. Hartmann:Apogenix: Research Funding. Kluge:Apogenix: Employment. Fricke:Apogenix GmbH: Employment, Equity Ownership. Debatin:Apogenix GmbH: Patents & Royalties, Research Funding.

Inducing the Tryptophan Catabolic Pathway, Indoleamine 2,3-Dioxygenase (IDO), for Suppression of Graft-Versus-Host Disease (GVHD) Lethality.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3547-3547
Author(s):  
Lisa Jasperson ◽  
Christoph Bucher ◽  
Angela Panoskaltsis-Mortari ◽  
Andrew Mellor ◽  
David H. Munn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intellectual Property ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Research Support ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ido Inhibitors

Abstract Abstract 3547 Poster Board III-484 During graft-versus-host disease (GVHD), donor T cells become activated and migrate to tissue sites. Previously, we demonstrated a crucial role for the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in GVHD regulation. Here, we show that upon arrival in the colon, activated donor T cells produced IFN-γ that upregulated IDO, causing T cell anergy and apoptosis. IDO induces GCN2 kinase, upregulating a T cell stress response implicated in IDO immunosuppression. Donor T cells did not require GCN2 kinase to respond to IDO, suggesting toxic IDO metabolites, and not tryptophan depletion, were responsible for suppression. When exogenous metabolites were administered, GVHD lethality was reduced. To determine if IDO could be induced pre-transplantation for enhanced GVHD suppression, we first determined whether antigen presenting cells (APCs) or epithelial cells were primarily responsible for IDO expression and subsequent GVHD suppression. Recipients with wild-type vs. IDO−/− APCs had increased survival, regardless of epithelial cell expression of IDO, suggesting that APCs were suitable targets for inducing IDO. Administration of an agonist to toll-like receptor (TLR)-7/8, a receptor expressed primarily on APCs, induced IDO and reduced injury in the colon, and ameliorated lethality. We conclude that IDO upregulation may have therapeutic potential for preventing GVHD in the clinic. Disclosures: Mellor: NewLink Genetics, Inc.: Consultancy, Intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receive consulting income and research support from NewLink Genetics, Inc., Research Funding. Munn:NewLink Genetics, Inc: Consultancy, Intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receive consulting income and research support from NewLink Genetics, Inc, Patents & Royalties, Research Funding.

scholarly journals The Innate Immune Sensor Sting Can Augment or Ameliorate Graft-Versus-Host Disease Dependent on the Genetic Disparity between Donors and Recipients

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 71-71
Author(s):  
Cameron S. Bader ◽  
Henry Barreras ◽  
Casey O. Lightbourn ◽  
Sabrina Copsel ◽  
Jeonghyun Ahn ◽  
...  
Keyword(s):  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cytokine Production ◽  
Host Disease ◽  
Graft Versus Host ◽  
Clinical Scores

Abstract Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCTs). Pre-HSCT conditioning typically consists of irradiation and drug administration which results in the death of rapidly dividing cells and the initiation of a cytokine storm, promoting activation and expansion of donor anti-host alloreactive T cells in HSCT recipients. However, the precise mechanism of cytokine production remains unclear. Cell death following pre-transplant conditioning has promoted the hypothesis that sensors of cytoplasmic DNA damage in GVHD target tissues contribute to cytokine production. One such sensor is Stimulator of Interferon Genes (STING) which following activation induces phosphorylation of IRF3 and IκBα. Although STING activation was recently reported to worsen GVHD after MHC-mismatched allo-HSCT (Fischer J, et al, Sci. Transl. Med. 2017), STING involvement in MHC-matched allo-HSCT has not yet been thoroughly evaluated. Here, using B6-STING knock-out recipients and either MHC-mismatched or matched ("MUD") donor strains we corroborate that STING deficiency worsens - but in contrast - ameliorates GVHD in the former and latter pre-clinical mouse models, respectively. To evaluate the effect of STING deficiency on GVHD after MHC-mismatched allo-HSCT, BALB/c BM + T cells were transplanted into 11.5Gy irradiated B6-WT and B6-STING-/- recipients. Consistent with previously reported results using B6-STINGgt/gt mice, STING-/- recipients experienced increased weight loss and GVHD clinical scores post-HSCT as well as decreased survival relative to WT recipients (Fig. 1A). Notably, when irradiation was given on day 0 instead of day -1 using the same donor/recipient combination no significant difference in GVHD was observed between WT and STING-/- recipients (Fig. 1B & 1E). We next investigated the role of STING after clinically relevant models of MHC-matched allo-HSCT. To assess for a role by STING immediately after HSCT, we examined cytokine mRNA expression 48 hrs. after transplant of LP/J BM + T cells → 8.5Gy irradiated B6-WT and B6-STING-/- recipients. Colonic tissue from STING-/- recipients had reproducibly &gt;2x reduction in IFNβ, TNFα and IL-6 mRNA compared to WT (Fig. 1C). Importantly, IFNβ is one of the major downstream effector molecules produced as a result of IRF3 phosphorylation, consistent with the notion that STING activation occurs shortly after conditioning and/or allo-HSCT. Notably, LN examination at this time demonstrated fewer donor CD8+ T cells and CD8+CD44hiCD62Llo cells in STING-/- vs WT recipients. In contrast to STING-/- recipients of MHC-mismatched HSCT, MHC-matched STING-/- HSCT recipients experienced decreased weight loss and GVHD clinical scores vs. WT mice. STING-/- recipients contained 20-50% fewer donor lymphocytes and a significantly reduced frequency of activated donor CD4+ and CD8+ T cells in lymphoid tissues on D7. Analysis of peripheral LN and spleen 1-3 mo. post-HSCT revealed a similar profile and a higher frequency of naïve T cells - consistent with their decreased clinical signs of disease. Histological examination of recipient skin also showed higher pathology scores in WT recipients relative to STING-/- recipients. These findings were corroborated using a second MUD model, i.e. C3H.SW → B6 (Fig. 1D). Furthermore, measurement of serum cytokines 6 wks. post-transplant showed that B6-STING-/- recipients had higher levels of the immunosuppressive cytokine IL-10. The effect of donor T cell dose was also examined. Increased donor T cell numbers resulted in enhanced GVHD clinical scores in STING-/- recipients, however, the GVHD remained less severe than that observed in WT. Notably, HSCT studies using fully reconstituted chimeric B6-CD45.1↔B6-STING-/- indicated that STING expression in non-hematopoietic tissues is important for the development of GVHD. In total, this is the first report we are aware of in which the same pathway appears to differentially impact the outcome of allogeneic HSCT based upon the genetic disparity across the transplant. These findings reveal that STING's contribution to the development of GVHD apparently differs depending on the presence or absence of an MHC-disparity between donors and recipients as well as the timing of the pathway's activation and HSCT. Disclosures Levy: Capricor Therapeutics: Consultancy; OccuRx: Research Funding; Shire: Research Funding; Allergan: Consultancy.

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