Expansion of CD4(+)CD25 (+) regulatory T cells from cord blood CD4(+) cells using the common γ-chain cytokines (IL-2 and IL-15) and rapamycin.

Rapamycin has important roles in the modulation of regulatory T cells. We tried to expand CD4(+)CD25(+) regulatory T cells (Treg cells) from umbilical cord blood (CB) CD4-positive cells using interleukin (IL)-15 or IL-2 with transforming growth factor (TGF)-ß and rapamycin. We were able to obtain more than 500-fold expansion of CD4(+)CD25(+) cells from CB CD4(+) cells using IL-15 and TGF-ß with rapamycin. These expanded CD4(+)CD25(+) cells expressed forkhead box P3 (FoxP3) mRNA at a level about 100-fold higher and could suppress allogeneic mixed lymphocyte culture (MLC) by more than 50%. Early after rapamycin stimulation, CB CD4(+) cells showed increased expression of FoxP3 and a serine/threonine kinase Pim2 and sustained expression of negative phosphoinositide 3-kinase regulator phosphatase and tensin homolog deleted on chromosome 10 (PTEN). On the other hand, CD4(+)CD25(+) cells expanded with rapamycin for 8 days showed much higher levels of FoxP3 mRNA expression and decreased expression of PTEN. A comparison of IL-15 stimulation and IL-2 stimulation showed slightly higher efficiency of IL-15 for expansion of CD4(+)CD25(+) cells, and for FoxP3 expression, IL-15 also showed significantly higher efficacy for inhibition of MLC. The combination of the common γ-chain cytokine IL-15, TGF-ß, and rapamycin may be a useful means for expanding Treg cells. Pim2 expression early after stimulation with rapamycin may be important for conferring rapamycin resistance for growth of Treg cells. IL-15 is not less useful than IL-2 for expansion of Treg cells.

Repeated donor lymphocyte infusions overcome a myeloid sarcoma of the stomach resulting from a relapse of acute myeloid leukemia after allogeneic cell transplantation in long-term survival of more than 10 years.

A patient with acute myeloid leukemia had a relapse with a myeloid sarcoma of the stomach 32 months after allogeneic bone marrow transplantation. The patient was treated with the first donor lymphocyte infusion (DLI) and one course of induction chemotherapy. Due to severe infectious complication after chemotherapy, the patient could not continue chemotherapy. Subsequently, the patient was treated with a total of 13 cycles of DLI at 1-2 month intervals. Complete remission was achieved and neither relapse nor graft versus host disease has occurred during a follow-up of more than 10 years.

[Cost benefit analysis for prophylactic use of itraconazole versus fluconazole after hematopoietic stem cell transplantation].

Systemic fungal infection (SFI) is now one of the main causes of death from infective complications after hematopoietic stem cell transplantation (HSCT) and the role of prophylaxis of fungal infection has been established. However, there is no evidence evaluating the cost-benefit ratio of SFI management in Japan. To estimate the medical costs on prophylaxis and treatment of SFI in HSCT, we embarked on a randomized control prospective study of the medical cost-benefit ratio comparing fluconazole with itraconazole for antifungal prophylaxis in 40 patients who received HSCT in our hospital. Despite the similarity of efficacy for prophylaxis, the median cost of itraconazole prophylaxis between Day-10 and Day+28 was significantly less than that of fluconazole. There are many patients who require an i.v. formulation because of non-compliance with oral administration after HSCT and these cases cause increased medical costs. Therefore, further investigation is needed not only regarding differences among prophylactic agents but also regarding differences in administration routes focusing on the cost-effectiveness of treatment.