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EP-4241080-B1 - METHODS FOR THE DIAGNOSIS AND THE TREATMENT OF GRAFT-VERSUS-HOST DISEASE

EP4241080B1EP 4241080 B1EP4241080 B1EP 4241080B1EP-4241080-B1

Inventors

  • GODEFROY, EMMANUELLE
  • CHEVALLIER, Patrice
  • ALTARE, Frédéric
  • JOTEREAU, FRANCINE

Dates

Publication Date
20260513
Application Date
20211103

Claims (6)

  1. A method of determining whether a subject has or is at a risk of developing graft-versus-host disease (GvHD) comprising the steps of: i) determining the level of CD73 expression by DP8α Tregs in a sample obtained from the subject, ii) comparing the level determined at step i) with a predetermined reference value wherein detecting differential between the level of CD73 expression by DP8α Tregs determined at step i) and the predetermined reference value is indicative of whether a subject has or is at a risk of developing graft-versus-host disease (GvHD) wherein the DP8α Tregs have a CD3+/CD4+/CD8α LOW/ CCR6+/CXCR6+ phenotype and wherein a low level of CD73 expression by DP8α Tregs compared to said predetermined reference value is indicative of whether a subject has or is at a risk of developing graft-versus-host disease (GvHD).
  2. The method of claim 1 wherein the sample is a blood sample.
  3. The method of claim 1 to 2 wherein the GvHD is acute graft-versus-host disease (aGvHD).
  4. The method of claim 1 to 3 wherein the sample is analyzed by flow cytometry.
  5. A therapeutically effective amount of an immunosuppressive agent or an infusion of DP8α Tregs exhibiting appropriate features for use in the treatment of graft-versus-host disease (GvHD) in a subject in need thereof wherein the DP8α Tregs have a CD3+/CD4+/CD8α LOW/ CCR6+/CXCR6+ phenotype and comprising a step of: i) Determining the level of CD73 expression by DP8α Tregs in a sample obtained from the subject, ii) Comparing the level determined at step i) with a predetermined reference value and iii) Administering said subject with a therapeutically effective amount of the said immunosuppressive agent or the said infusion of DP8α Tregs exhibiting appropriate features when the level of CD73 expression by DP8α Tregs is lower than the predetermined reference value wherein the immunosuppressive agent includes cytokines, corticoids, cytostatics, or tyrosine kinase inhibitors.
  6. A therapeutically effective amount of an immunosuppressive agent or an infusion of DP8α Tregs exhibiting appropriate features or DP8α target antigens (F. prausnitzii- derived) in the form of peptides, proteins, or even bacteria/probiotics for use according to the claim 5 wherein the GvHD is acute graft-versus-host disease (aGvHD).

Description

FIELD OF THE INVENTION: The invention relates to methods for the prediction and the treatment of risk of acute graft versus host disease. BACKGROUND OF THE INVENTION: Hematological malignancies are currently treated with myeloablation conditioning regimens, followed by infusion of allogeneic hematopoietic stem cell transplantation (allo-HSCT)1, presently obtained by G-CSF-induced mobilization in donor's blood. Allo-reactive donors' T cells contained in the graft contribute to disease control through tumor cell destruction. However, in 30-50% of patients, these cells also induce acute graft-versus-host disease (aGvHD)2, a potentially deadly complication whereby graft-derived cells attack healthy host tissues. While steroids remain the first-line treatment for aGvHD, new treatments are needed to improve allo-HSCT outcomes and reduce steroid complications. Increasing evidences suggest that gut microbiota3 and, in some mouse studies, regulatory T cells (TREGS)4 are involved in GvHD prevention. Furthermore, an alteration in adenosine/purinergic signaling, sequentially driven by CD39 and CD73 ectonucleotidases, which in vivo degrade pro-inflammatory ATP, resulting in the production of immunosuppressive adenosine, has been proposed to play a role in GvHD occurrence5,6. Accordingly, there is therefore still a need for methods for prognosing, diagnosing and/or treating graft-versus-host disease (GvHD) which methods are non-invasive, reliable and/or easy to carry out. Interestingly, the inventors have identified a novel FoxP3-negative and IL-10-secreting TREG subset, expressing high levels of both CD39 and CD73 and that functionally depends on this purinergic pathway, induced by the gut commensal Faecalibacterium prausnitzii7-9. The inventors therefore postulated that F. prausnitzii-reactive DP8α TREGS could bridge microbiota dysbiosis and GvHD occurrence. In support of this, decreased levels of Clostridium bacteria, especially Faecalibacterium spp, have been associated with greater aGvHD risk10. Moreover, mice gavaged with TREG-inducing Clostridia displayed milder GvHD and improved survival11. Here, the inventors investigated the status of microbiota-reactive DP8α Tregs in hematological malignancies treated by allo-HSCT, taking advantage of their unique CD3+/CD4+/CD8αLOW/CCR6+/CXCR6+ phenotype. SUMMARY OF THE INVENTION: The invention relates to methods for the prediction and the treatment of risk of acute graft versus host disease. In particular, the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION: Allogeneic stem cell transplantation (allo-HSCT) to treat hematological malignancies can induce life-threatening complications, such as graft-versus-host disease (GvHD). Increasing evidences suggest that gut microbiota composition and the activity of regulatory T cells (TREGS) are involved in GvHD prevention. Furthermore, an alteration in the purinergic pathway sequentially driven by CD39 and CD73 ectonucleotidases, which in vivo degrade pro-inflammatory ATP into immunosuppressive adenosine, has also been proposed to be involved in GvHD occurrence. The inventors have identified a novel TREG subset, named DP8α, characterized by its CD3+/CD4+/CD8αLOW/CCR6+/CXCR6+ phenotype and a TCR-specificity for the gut bacterium Faecalibacterium prausnitzii. Moreover, their regulatory/suppressive function in vitro relies on the CD39/CD73 pathway, further advocating their study in the GvHD context. Strikingly, using flow cytometry, then inventors revealed here that a marked CD73-deficiency, specifically on DP8α Tregs in patients' blood at d30 after allo-HSCT, was strongly associated with acute GvHD occurrence. This was consistently observed across heterogenous clinical conditions (diseases/transplants/conditioning/prophylaxis). The inventor also formally established that blocking the CD73 function of DP8α Treg clones completely suppressed their ability to inhibit effector T cell proliferation in vitro. The inventors demonstrated that an alteration of CD73-mediated regulatory function of DP8α Tregs could contribute to the acute GvHD pathophysiology. These results could open the way to strategies to, not only predict, but also treat acute GvHD through modulation of DP8α Treg activity in this patients' population. Diagnostics methods according to the invention The scope of the invention is defined by the appended claims. The present disclosure relates to a method of determining whether a subject has or is at a risk of developing acute graft-versus-host disease (aGvHD) comprising the steps of: i) determining the level of CD73 expression by DP8α TREGS in a sample obtained from the subject, ii) comparing the level determined at step i) with a predetermined reference value wherein detecting differential between the level of CD73 expression by DP8α TREGS determined at step i) and the predetermined reference value is indicative of whether a subject has or is at a risk of developing acute graft-versus-host disease