Novel mechanisms of graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT)

• Project/Area Number: 17H06537
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Yamagata University
• Principal Investigator: TOBAI TOMOMI 山形大学, 医学部, 講師 (40802111)
• Research Collaborator: Pavan Reddy
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 移植片対宿主病 / NLRP6 / T細胞 / 同種移植 / 同種造血幹細胞移植 / マウス骨髄移植モデル / 移植片対宿主病（GVHD) / インフラマゾーム / 移植関連合併症 / 血液内科学 / 同種造血細胞移植 / 移植免疫学

Outline of Final Research Achievements

NOD-like receptor family pyrin domain containing 6 (NLRP6) plays an important role in regulating gut microbiota and homeostasis. However, whether NLRP6 regulates T cell functions remains unknown. We found that naive T cells express NLRP6 but the absence of NLRP6 did not affect the numbers and the subpopulation of T cells, such as regulatory T cells. The expression of NLRP6 in T cells was dramatically increased following stimulation with anti-CD3/CD28 antibodies. NLRP6 deficient T cells exhibited significantly greater proliferation after non-specific T cell receptor stimulation as well as mixed lymphocyte reaction (MLR). We also demonstrated that the absence of NLRP6 on donor T cells exacerbated graft-versus -host disease (GVHD) in multiple irradiated and non-irradiated BMT models. We suggest that NLRP6 is a potentially novel negative regulator of T cell responses, and maybe a useful target to mitigate GVHD.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、炎症反応においてNLRP6がインフラマゾーム依存性メカニズムを持つだけでなく、非依存性メカニズムを持っていることを明らかにしたことにより、NLRP6が種々の免疫反応において多種多彩な機能を持つことを明確に示すことができた。NLRP6の免疫細胞における機能解析を発展させる事で、敗血症などの炎症性疾患のみならず移植片対宿主病や自己免疫疾患、さらには悪性腫瘍内の微小環境下における免疫抑制機構の解明にも貢献すると考えられる。NLRP6の制御機構を明らかにする事で、将来的な免疫チェックポイントや免疫抑制剤の開発につながる可能性がある。

Research Products

• [Int'l Joint Research] University of Michigan(米国)
• [Int'l Joint Research] ミシガン大学医学部内科学講座血液・腫瘍内科(米国)
• [Journal Article] Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition. (2019)
  • Author(s): Toubai T, Fujiwara H, Rossi C, Riwes M, Tamaki H, Zajac C, Liu C, Mathew AV, Byun J, Oravecz-Wilson K, Matsuda I, Sun Y, Peltier D, Wu J, Chen J, Seregin S, Henig I, Kim S, Brabbs S, Pennathur S, Chen G, Reddy P.
  • Journal Title: Nat Microbiol Volume: 4 Issue: 5 Pages: 800-812
  • DOI: 10.1038/s41564-019-0373-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation. (2018)
  • Author(s): Toubai T, Tamaki H, Peltier DC, Rossi C, Oravecz-Wilson K, Liu C, Zajac C, Wu J, Sun Y, Fujiwara H, Henig I, Kim S, Lombard DB, Reddy P.
  • Journal Title: J Immunol Volume: 201 Issue: 11 Pages: 3443-3445
  • DOI: 10.4049/jimmunol.1800148
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microbial metabolite sensor GPR43 controls severity of experimental GVHD. (2018)
  • Author(s): Fujiwara H, Docampo MD, Riwes M, Peltier D, Toubai T, Henig I, Wu SJ, Kim S, Taylor A, Brabbs S, Liu C, Zajac C, Oravecz-Wilson K, Sun Y, Nunez G, Levine JE, van den Brink MRM, Ferrara JLM, Reddy P.
  • Journal Title: Nat Commun Volume: 9 Issue: 1 Pages: 3674-3674
  • DOI: 10.1038/s41467-018-06048-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Murine Models of Steroid Refractory Graft-versus-Host Disease. (2018)
  • Author(s): Toubai T, Rossi C, Tawara I, Liu C, Zajac C, Oravecz-Wilson K, Peltier D, Sun Y, Fujiwara H, Wu SR, Riwes M, Henig I, Kim S, Reddy P.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 12475-12475
  • DOI: 10.1038/s41598-018-30814-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] I. 移植片対宿主病(GVHD)の病態解明 3)移植片対宿主病（GVHD）におけるバイオマーカー. (2018)
  • Author(s): 東梅友美
  • Journal Title: 血液フロンティア Volume: 28 Pages: 39-48
• [Journal Article] Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells. (2017)
  • Author(s): Sun Y, Iyer M, McEachin R, Zhao M, Wu YM, Cao X, Oravecz-Wilson K, Zajac C, Mathewson N, Wu SJ, Rossi C, Toubai T, Qin ZS, Chinnaiyan AM, Reddy P.
  • Journal Title: J Innate Immune Volume: 9 Issue: 2 Pages: 126-144
  • DOI: 10.1159/000450681
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation. (2017)
  • Author(s): Wu SJ, Niknafs YS, Kim SH, Oravecz-Wilson K, Zajac C, Toubai T, Sun Y, Prasad J, Peltier D, Fujiwara H, Hedig I, Mathewson ND, Khoriaty R, Ginsburg D, Reddy P.
  • Journal Title: Cell Rep Volume: 19 Issue: 13 Pages: 2645-2656
  • DOI: 10.1016/j.celrep.2017.06.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] STAT3 Expression in Host Myeloid Cells Controls GVHD Severity. (2017)
  • Author(s): Nieves EC, Toubai T, Peltier DC, Oravecz-Wilson K, Liu C, Tamaki H, Sun Y, Reddy P.
  • Journal Title: Biol Blood Marrow Transplant Volume: 23 Issue: 10 Pages: 1622-1630
  • DOI: 10.1016/j.bbmt.2017.06.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Siglec-G represses DAMP mediated effects on T cells. (2017)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Zajac C, Liu C, Braun T, Fujiwara H, Wu J, Sun Y, Brabbs S, Tamaki H, Magenau J, Zheng P, Liu Y, Reddy P.
  • Journal Title: JCI Insight Volume: 2 Issue: 14
  • DOI: 10.1172/jci.insight.92293
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IAPs protect host target tissues from graft-versus-host disease in mice. (2017)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Liu C, Zajac C, Wu SJ, Sun Y, Fujiwara H, Tamaki H, Peltier D, Riwes M, Henig I, Brabbs S, Duckett CS, Wang S, Reddy P.
  • Journal Title: Blood Advances Volume: 1 Issue: 19 Pages: 1517-1532
  • DOI: 10.1182/bloodadvances.2017004242
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Donor T cell independent mechanism may contribute to enhancing steroid refractory GVHD in murine models. (2019)
  • Author(s): Toubai T, Rossi C, Tawara I, Liu C, Zajac C, Oravecz-Wilson K, Peltier D, Sun Y, Fujiwara F, Wu SR, Riwes M, Henig I, Kim S, Suto M, Ishizawa K, Reddy P.
  • Organizer: 2019 Transplantation & Cellular Therapy Meetings
  • Int'l Joint Research
• [Presentation] Donor T Cell Independent Mechanism Is Critical for Mediating Steroid Refractory Gvhd in Murine Models. (2019)
  • Author(s): Toubai T, Rossi C, Tawara I, Liu C, Zajac C, Oravecz-Wilson K, Peltier D, Sun Y, Fujiwara F, Wu SR, Riwes M, Henig I, Kim S, Suto M, Ishizawa K, Reddy P.
  • Organizer: The 45th Annual Meeting of the European Society of Blood and Marrow Transplantation
  • Int'l Joint Research
• [Presentation] Mitochondrial deacetylase SIRT3 regulates donor T cellactivation in GVHD. (2019)
  • Author(s): Toubai T, Peltier D, Tamaki H, Rossi C, Reddy P.
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] Murine models of steroid refractory GVHD. (2019)
  • Author(s): Suto M, Eri M, Yanagiya R, Takabatake I, Kikuchi Y, Sakurai M, Kimura A, Ishizawa Y, Tawara I, Ishizawa K, Reddy P, Toubai T.
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] Update on findings from mouse models of acute GVHD pathophysiology (2018)
  • Author(s): Tomomi Toubai
  • Organizer: The International Congress of BMT 2018
  • Int'l Joint Research / Invited
• [Presentation] Murine models of establishing steroid refractory GVHD. (2018)
  • Author(s): Toubai T, Rossi C, Tawara I, Liu C, Zajac C, Oravecz-Wilson K, Peltier D, Sun Y, Fujiwara H, Wu J, Rives M, Henig I, Kim S, Ishizawa K, Reddy P
  • Organizer: 23th Congress of the European Hematology Association (EHA)
  • Int'l Joint Research
• [Presentation] Donor T Cell Independent Mechanism Is Critical for Mediating Steroid Refractory Gvhd in Murine Models. (2018)
  • Author(s): Toubai T, Rossi C, Tawara I, Liu C, Zajac C, Oravecz-Wilson K, Peltier D, Sun Y, Fujiwara F, Riwes M, Henig I, Kim S, Suto M, Ishizawa K, Reddy P.
  • Organizer: 60th Annual Meeting of American Society of Hematology (ASH)
  • Int'l Joint Research
• [Presentation] Inhibitors of apoptosis proteins (IAPs) are required for protecting gastrointestinal GVHD. (2018)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Zajac C, Chen L, Tamaki H, Ishizawa K, Reddy P.
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] Murine models of steroid refractory graft-versus-host disease. (2018)
  • Author(s): Toubai T, Rossi C, Tawara I, Ishizawa K, Reddy P.
  • Organizer: 第80回日本血液学会総会
• [Presentation] Inhibitors of apoptosis proteins (IAPs) modulate gastrointestinal GVHD in murine experimental BMT models. (2017)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Chen L, Zajac C, Wu J, Sun Y, Fujiwawa H, Tamaki H, Peltier D, Riwes M, Hening I, Brabbs S, Reddy P.
  • Organizer: 22th Congress of the European Hematology Association (EHA).
  • Int'l Joint Research
• [Presentation] Metabolic reprogramming of dendritic cells is controlled by the Mir-142. (2017)
  • Author(s): Sun Y, Saunders T, Oravecz-Wilson K, Bridges S, McEachin R, Wu J, Kim S, Zajac C, Toubai T, Fujiwara H, Henig I, Peltier D, Reddy P.
  • Organizer: 59th Annual Meeting of American Society of Hematology (ASH)
  • Int'l Joint Research
• [Presentation] Siglec-G-CD24 pathway regulates DAMP medated donor T cell activation. (2017)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Zajac C, Chen L, Fujiwara H, Wu J, Tamaki H, Magneau J, Reddy P.
  • Organizer: 第79回日本血液学会総会
• [Presentation] Inhibitors of apoptosis proteins (IAPs) are required for protecting gastrointestinal GVHD. (2017)
  • Author(s): Toubai T, Rossi C, Oravecz-Wilson K, Zajac C, Chen L, Tamaki H, Ishizawa K, Reddy P.
  • Organizer: 第40回日本造血細胞移植学会総会