Donor pretreatment with progenipoietin-1 is superior to granulocyte colony-stimulating factor in preventing graft-versus-host disease after allogeneic stem cell transplantation.

Abstract

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.

• Authors: Kelli P A MacDonald, Vanessa Rowe, Cheryl Filippich, Ranjeny Thomas, Andrew D Clouston, Joseph K Welply, Derek N J Hart, James L M Ferrara, Geoffrey R Hill
• Journal: Blood (Blood) Vol. 101 Issue 5 Pg. 2033-42 (Mar 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12393418 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Colony-Stimulating Factors
• Cytokines
• Recombinant Proteins
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha
• progenipoietin-1
• Interleukin-10
• Granulocyte Colony-Stimulating Factor

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology)
• Cell Adhesion
• Cell Adhesion Molecules (biosynthesis, genetics)
• Cell Lineage
• Cell Transplantation (adverse effects)
• Clonal Anergy
• Colony-Stimulating Factors (therapeutic use)
• Cytokines (metabolism)
• Dendritic Cells (drug effects, immunology, transplantation)
• Female
• Gastrointestinal Diseases (immunology, prevention & control)
• Gene Expression Regulation (drug effects)
• Graft vs Host Disease (prevention & control)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Interleukin-10 (biosynthesis, genetics)
• Lymphocyte Depletion
• Mice
• Mice, Inbred C57BL
• Radiation Chimera
• Recombinant Proteins (pharmacology, therapeutic use)
• Spleen (cytology, immunology)
• T-Lymphocyte Subsets (immunology, transplantation)
• Transforming Growth Factor beta (biosynthesis, genetics)
• Transplantation, Homologous (adverse effects)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)