Donor pretreatment with progenipoietin-1 is superior to granulocyte colony-stimulating factor in preventing graft-versus-host disease after allogeneic stem cell transplantation.
The granulocyte colony-stimulating factor (G-CSF) and Flt-3 receptor agonist progenipoietin-1 (ProGP-1) has potent effects on dendritic cell (DC) expansion and may be an alternative to G-CSF for the mobilization of stem cells for allogeneic stem cell transplantation (SCT). We studied the ability of stem cell grafts mobilized with this agent to induce graft-versus-host disease (GVHD) to minor and major histocompatibility antigens in the well-described B6 --> B6D2F1 SCT model. ProGP-1, G-CSF, or control diluent was administered to donor B6 mice. ProGP-1 expanded all cell lineages in the spleen, and unseparated splenocytes from these animals produced large amounts of interleukin 10 (IL-10) and transforming growth factor beta (TGFbeta) whereas the expression of T-cell adhesion molecules was diminished. Transplantation survival was 0%, 50%, and 90% in recipients of control-, G-CSF-, and ProGP-1-treated allogeneic donor splenocytes, respectively (P <.0001). Donor pretreatment with ProGP-1 allowed a 4-fold escalation in T-cell dose over that possible with G-CSF. Donor CD4 T cells from allogeneic SCT recipients of ProGP-1 splenocytes demonstrated an anergic response to host antigen, and cytokine production (interferon gamma [IFNgamma], IL-4, and IL-10) was also reduced while CD8 T-cell cytotoxicity to host antigens remained intact. Neither CD11c(hi) DCs nor CD11c(dim)/B220(hi) DCs from ProGP-1-treated animals conferred protection from GVHD when added to control spleen. Conversely, when equal numbers of purified T cells from control-, G-CSF-, or ProGP-1-treated allogeneic donors were added to allogeneic T-cell-depleted control spleen, survival at day 60 was 0%, 15%, and 90%, respectively (P <.0001). The improved survival in recipients of ProGP-1 T cells was associated with reductions in systemic tumor necrosis factor alpha generation and GVHD of the gastrointestinal tract. We conclude that donor pretreatment with ProGP-1 is superior to G-CSF for the prevention of GVHD after allogeneic SCT, primarily due to incremental affects on T-cell phenotype and function.
MacDonald
Kelli P A
KP
The Queensland Institute of Medical Research, and the Department of Pathology, University of Queensland, Herston, Australia.
Rowe
Vanessa
V
Filippich
Cheryl
C
Thomas
Ranjeny
R
Clouston
Andrew D
AD
Welply
Joseph K
JK
Hart
Derek N J
DN
Ferrara
James L M
JL
Hill
Geoffrey R
GR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D019070:Cell Lineage; D017690:Cell Transplantation / Q000009:adverse effects; D017635:Clonal Anergy; D003115:Colony-Stimulating Factors / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D005260:Female; D005767:Gastrointestinal Diseases / Q000276:immunology / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D015815:Cell Adhesion Molecules; D003115:Colony-Stimulating Factors; D016207:Cytokines; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C434603:progenipoietin-1; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor