Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester

• Published in: The Journal of clinical investigation 1986-11, Vol.78 (5), p.1415-1420
• Main Authors: CHARLEY, M, THIELE, D. L, BENNETT, M, LIPSKY, P. E
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow Transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Dipeptides - therapeutic use; Female; Graft Survival - drug effects; Graft vs Host Disease - prevention & control; Lymphocyte Transfusion; Lymphocytes - drug effects; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Spleen - radiation effects; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI112730

Graft vs. host disease (GVHD) remains one of the main problems associated with bone marrow transplantation. The current studies were undertaken to determine whether treatment of the donor inoculum with the anticytotoxic cell compound L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) would alter the development of GVHD in a murine model. Irradiated recipient mice transplanted with a mixture of control bone marrow and spleen cells from naive semiallogeneic donors died rapidly from GVHD, whereas the recipients of cells incubated with 250 microM Leu-Leu-OMe all survived. In addition, Leu-Leu-OMe treatment of cells obtained from donors immunized against host alloantigens resulted in significantly prolonged survival. Phenotypic characterization of spleen cells from the various groups of mice that had received Leu-Leu-OMe-treated cells and survived consistently revealed the donor phenotype. Treatment of marrow cells with 250 microM Leu-Leu-OMe appeared to have no adverse effects on stem cell function. Erythropoiesis was undiminished, as assayed by splenic 5-iodo-2'-deoxyuridine-125I uptake. Moreover, granulocytic and megakaryocytic regeneration were histologically equivalent in the spleens of recipients of control or Leu-Leu-OMe-treated cells. Treatment of the donor inoculum with Leu-Leu-OMe thus prevents GVHD in this murine strain combination with no apparent stem cell toxicity.