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Reduction of lethal graft-versus-host disease: transplantation of cultured murine bone marrow across minor
Abstract:
The murine bone marrow culture technique was used to prepare donor marrow for bone marrow transplantation across minor histocompatibility complex differences. Previous studies have shown that theta-positive cells are rapidly lost from such cultures and that transplantation of cultured marrow across major histocompatibility complex differences results in a delay in the development of lethal graft-v-host disease (GVHD). In this study, a total of 1 to 2 X 10(7) nonadherent cells (740 to 1560 CFUs [colony-forming units]) from three-day-old cultures were used as a source of donor marrow. Three strain combinations were evaluated; LP/J into C57BL/6; BIO.BR into CBA/J; and C57BL/6 into LP/J. Donor mice were immunized with recipient spleen cells prior to culture in order to increase the graft-v-host response. For LP/J marrow into C57BL/6 mice, 5 X 10(7) donor spleen cells transplanted along with the marrow were needed to induce lethal GVHD. However, lethal GVHD was seen without the addition of spleen cells for BIO.BR into CBA/J and C57BL/6 into LP/J strain combinations. Most animals receiving fresh marrow were dead of GVHD five weeks after transplantation. With the use of cultured marrow the three-month survival was 80%, 51%, and 93%, respectively, for LP/J into C57BL/6, BIO.BR into CBA/J, and C57BL/6 into LP/J strain combinations. Long-term donor engraftment in all recipient animals receiving cultured marrow was confirmed by analyzing hemoglobin polymorphisms between the strain combinations. These results demonstrate that in contrast to transplantation across major histocompatibility complex differences, the use of cultured cells for bone marrow transplantation across minor histocompatibility complex differences allows for engraftment while reducing the risk of lethal GVHD.
Insights
Cultured bone marrow cells reduce lethal graft-versus-host disease (GVHD) in mice transplanted across minor histocompatibility differences. This method allows for successful engraftment while significantly improving survival rates compared to fresh marrow.
Area of Science:
- Immunology
- Transplantation Biology
- Hematology
Background:
- Bone marrow transplantation (BMT) across minor histocompatibility complex (mHDC) differences can lead to lethal graft-versus-host disease (GVHD).
- Previous research indicated that culturing bone marrow cells reduces theta-positive cells, potentially mitigating GVHD.
- GVHD poses a significant challenge in mHDC-mismatched BMT, impacting patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of using cultured murine bone marrow cells for BMT across mHDC differences.
- To assess the impact of marrow culture on GVHD incidence and severity.
- To determine long-term donor engraftment rates following BMT with cultured marrow.
Main Methods:
- Murine bone marrow cells were cultured for three days to remove theta-positive cells.
- Three different mouse strain combinations with mHDC differences were used for transplantation.
- Donor mice were immunized with recipient spleen cells to enhance the GVHD response.
- Nonadherent cultured cells or fresh marrow were transplanted, and survival was monitored.
Main Results:
- Transplantation of fresh marrow resulted in high mortality due to lethal GVHD within five weeks.
- Use of cultured marrow significantly improved three-month survival rates: 80% (LP/J into C57BL/6), 51% (BIO.BR into CBA/J), and 93% (C57BL/6 into LP/J).
- Long-term donor engraftment was confirmed in all recipients of cultured marrow via hemoglobin polymorphism analysis.
Conclusions:
- Bone marrow transplantation using cultured cells across mHDC differences effectively reduces lethal GVHD.
- This technique facilitates donor cell engraftment while minimizing the risk of severe GVHD.
- Cultured marrow represents a promising strategy for improving outcomes in mHDC-mismatched BMT.