CpG-induced myeloid CD11b+Gr-1+ cells efficiently suppress T cell-mediated immunoreactivity and graft-versus-host disease in a murine model of allogeneic cell therapy.
Transplantation of mismatched allografts in irradiated recipients results in lethal graft- versus-host disease (GVHD). In our study, pretransplantation donor treatment with CpG, administered either alone or emulsified in incomplete Freund's adjuvant, efficiently prevented GVHD in sublethally irradiated recipients of haploidentical (H-2(b) into H-2(b/d)) and fully mismatched (H-2(b) into H-2(d)) allografts. CpG treatment of donor mice caused an accumulation of double-positive CD11bGr-1 cells in their blood and spleens, whereas treatment with CpG+IFA resulted in an even greater accumulation of these cells. Isolated CD11b(+) cells from the spleens of CpG+IFA-treated mice efficiently suppressed alloreactivity in vitro (> 92%), as determined by co-culturing these cells in mixed lymphocyte reactions. After CpG+IFA treatment, a T cell-depleted fraction enriched with CD11b(+)Gr-1(+) cells, acting as myeloid suppressor cells, was able to efficiently prevent GVHD induced by naïve T cells in the sublethally irradiated recipients: 20/21 mice remained GVHD-free survivors for more than 200 days. Splenocytes from CpG+IFA-treated mice displayed enhanced interleukin (IL)-6, IL-10, and interferon-gamma production, reduced T cell allogeneic and mitogenic responses, as well as failure of T cells to induce GVHD. In summary, CpG treatment led to impaired T cell function, enriched myeloid suppressor cells and regulatory cytokine production, which together appear to suppress alloreactivity and protect against the development of GVHD. We hypothesize that similar immunoregulatory effects could be applied experimentally in a clinical setting when inhibition of alloreactivity is required in recipients of stem cell allografts.
Morecki
Shoshana
S
Department of Bone Marrow Transplantation, Cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel. Electronic address: morecki@hadassah.org.il.
Gelfand
Yael
Y
Department of Bone Marrow Transplantation, Cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.
Yacovlev
Elena
E
Department of Bone Marrow Transplantation, Cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.
Eizik
Osnat
O
Department of Bone Marrow Transplantation, Cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.
Shabat
Yehudit
Y
Department of Bone Marrow Transplantation, Cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel.
Slavin
Shimon
S
The International Centre for Cell Therapy and Cancer, Tel Aviv (Souraski) Medical Center, Tel Aviv 64239, Israel.
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D039481:CD11b Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019707:Receptors, Chemokine; D013154:Spleen / Q000276:immunology / Q000473:pathology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous
D000276:Adjuvants, Immunologic; D039481:CD11b Antigen; C408982:CPG-oligonucleotide; C503133:Gr-1 protein, mouse; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D019707:Receptors, Chemokine; D016753:Interleukin-10; D005620:Freund's Adjuvant