IL-2-targeted therapy ameliorates the severity of graft-versus-host disease: ex vivo selective depletion of host-reactive T cells and in vivo therapy.
T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion.
GASR Biotechnology, Kfar-Saba, Israel. shai@gasr-bio.com
Shai
S
Yarkoni
Tatyana B
TB
Prigozhina
Shimon
S
Slavin
Nadir
N
Askenasy
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
D015703:Antigens, CD; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D053148:Caspase 3