Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced-Intensity Allogeneic Hemopoietic Cell Transplantation.

Abstract

BACKGROUND:

Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood.

METHODS:

We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI).

RESULTS:

The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice.

CONCLUSIONS:

We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.

• Authors: Kifah Shahin, Zamil Mattar, Pablo Silveira, Wei-Hsun Hsu, Linda Bendall, Derek Hart, Kenneth F Bradstock
• Journal: Transplantation (Transplantation) Vol. 101 Issue 11 Pg. 2695-2704 (11 2017) ISSN: 1534-6080 [Electronic] United States
• PMID: 28319565 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myeloablative Agonists
• Cyclophosphamide
• Vidarabine
• fludarabine

Topics

• Animals
• Bone Marrow Diseases (blood, immunology, prevention & control)
• CD8-Positive T-Lymphocytes (immunology)
• Cyclophosphamide (administration & dosage)
• Disease Models, Animal
• Drug Administration Schedule
• Female
• Graft vs Host Disease (blood, immunology, prevention & control)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Histocompatibility
• Major Histocompatibility Complex
• Mice, Inbred BALB C
• Myeloablative Agonists (administration & dosage)
• Spleen (immunology)
• Time Factors
• Transplantation Chimera (immunology)
• Transplantation Conditioning (adverse effects, methods)
• Transplantation, Homologous
• Vidarabine (administration & dosage, analogs & derivatives)
• Whole-Body Irradiation (adverse effects)