Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant immunosuppressive drugs incompletely control GVHD and increase susceptibility to opportunistic infections. In this study, we used flagellin, a TLR5 agonist protein (∼50 kDa) extracted from bacterial flagella, as a novel experimental treatment strategy to reduce both acute and chronic GVHD in allogeneic HSCT recipients. On the basis of the radioprotective effects of flagellin, we hypothesized that flagellin could ameliorate GVHD in lethally irradiated murine models of allogeneic HSCT. Two doses of highly purified flagellin (administered 3 h before irradiation and 24 h after HSCT) reduced GVHD and led to better survival in both H-2(b) → CB6F1 and H-2(K) → B6 allogeneic HSCT models while preserving >99% donor T cell chimerism. Flagellin treatment preserved long-term posttransplant immune reconstitution characterized by more donor thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells and significantly enhanced antiviral immunity after murine CMV infection. The proliferation index and activation status of donor spleen-derived T cells and serum concentration of proinflammatory cytokines in flagellin-treated recipients were reduced significantly within 4 d posttransplant compared with those of the PBS-treated control recipients. Allogeneic transplantation of radiation chimeras previously engrafted with TLR5 knockout hematopoietic cells showed that interactions between flagellin and TLR5 expressed on both donor hematopoietic and host nonhematopoietic cells were required to reduce GVHD. Thus, the peritransplant administration of flagellin is a novel therapeutic approach to control GVHD while preserving posttransplant donor immunity.
Division of Stem Cell and Bone Marrow Transplantation, Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Mohammad S
MS
Hossain
David L
DL
Jaye
Brian P
BP
Pollack
Alton B
AB
Farris
Malefa L
ML
Tselanyane
Ebenezer
E
David
John D
JD
Roback
Andrew T
AT
Gewirtz
Edmund K
EK
Waller
D016475:3T3 Cells; D000208:Acute Disease; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002908:Chronic Disease; D005408:Flagellin / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015994:Incidence; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology; D012720:Severity of Illness Index; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000502:physiology*; D014184:Transplantation, Homologous
D000998:Antiviral Agents; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin