Treatment of severe life-threatening graft-versus-host disease by autologous peripheral blood stem cell transplantation using a nonmyeloablative preconditioning regimen.
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Adult↗
Biomedical subjects
Kazuhiro Ikegame
Publications and source records attributed to Kazuhiro Ikegame.
The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia.
In acute-type leukemia, no method for the prediction of relapse following allogeneic stem cell transplantation based on minimal residual disease (MRD) levels is established yet. In the present study, MRD in 72 cases of allogeneic transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by quantitating the transcript of WT1 gene, a "panleukemic MRD marker," using reverse transcriptase-polymerase chain reaction. Based on the negativity of expression of chimeric genes, the background level of WT1 transcripts in bone marrow following allogeneic transplantation was significantly decreased compared with the level in healthy volunteers. The probability of relapse occurring within 40 days significantly increased step-by-step according to the increase in WT1 expression level (100% for 1.0 x 10(-2)-5.0 x 10(-2), 44.4% for 4.0 x 10(-3)-1.0 x 10(-2), 10.2% for 4.0 x 10(-4)-4.0 x 10(-3), and 0.8% for < 4.0 x 10(-4)) when WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse increased exponentially with a constant doubling time. The doubling time of the WT1 level in patients for whom the discontinuation of immunosuppressive agents or donor leukocyte infusion was effective was significantly longer than that for patients in whom it was not (P <.05). No patients with a short doubling time of WT1 transcripts (< 13 days) responded to these immunomodulation therapies. These findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene markers.
Acute Disease↗
Combination of tacrolimus, methotrexate, and methylprednisolone prevents acute but not chronic graft-versus-host disease in unrelated bone marrow transplantation.
BACKGROUND: Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors. METHODS: All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29. RESULTS: Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD. CONCLUSIONS: An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.
Acute Disease↗
Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers.
Expression of the Wilms' tumor gene WT1 in de novo lung cancer was examined using quantitative real-time RT-PCR and immunohistochemistry. Overexpression of the WT1 gene was detected by RT-PCR in 54/56 (96%) de novo non-small cell lung cancers examined and confirmed by detection of WT1 protein with an anti-WT1 antibody. Overexpression of the WT1 gene was also demonstrated in 5/6 (83%) de novo small cell lung cancers by immunohistochemistry. Furthermore, when the WT1 gene was examined for mutations by direct sequencing of genomic DNA in 7 lung cancers, no mutations were found. These results suggest that the nonmutated, wild-type WT1 gene plays an important role in tumorigenesis of de novo lung cancers and may provide us with the rationale for new therapeutic strategies for lung cancer targeting the WT1 gene and its products.
Aged↗
Antibodies against hepatoma-derived growth factor and mucosal repair in ulcerative colitis.
Ulcerative colitis is a chronic inflammatory disease of colonic mucosa in which the pathogenesis of any immunological disorders would likely be related. Various circulating autoantibodies have been reported in patients with ulcerative colitis, although their possible roles in this disease process have not yet been clarified. Autoantibody against hepatoma-derived growth factor (HDGF) was detected at high frequency in the serum of patients with ulcerative colitis, especially in patients with total colitis and left-sided colitis. In pursuit of the possible role of anti-HDGF autoantibody in the pathogenesis, we investigated HDGF expression in the intestinal mucosa by Western blotting and immunohistochemistry and the effects of recombinant proteins and antirecombinant HDGF antibody on the proliferation of the colonic epithelial cell-derived cell line, HT-29. HDGF was expressed in the nucleus of the colonic epithelial cells dominantly in the bottom of the crypts. Recombinant HDGF stimulated the proliferation of HT-29 cells significantly, although its effects were small, about 20% greater than the control at 100 ng/ml. On the other hand, the polyclonal IgG antibody against recombinant HDGF generated by rabbits suppressed their proliferation almost completely at 250 microg/ml. These findings suggest that HDGF plays an important role in epithelial cell renewal of intestinal crypts as a growth and survival factor, and that autoantibody against HDGF may delay mucosal healing and repair by inhibiting the stimulatory effects of HDGF on epithelial cell proliferation, resulting in a chronic process of colonic mucosal injury.
Autoantibodies↗
The effect on the proliferation and apoptosis of alloreactive T cells of cell dose in a murine MHC-mismatched hematopoietic cell transplantation model.
Activation-induced cell death (AICD) of lymphocytes is an apoptotic pathway involved in the control of T-cell homeostasis. The magnitude of graft-vs.-host disease (GVHD) following allogeneic hematopoietic cell transplantation may be attenuated by the enhancement of AICD. The aim of the present study was to clarify the effect of T cell dose upon the fate (proliferation or apoptosis) of individual activated T cells in a murine GVHD model. To this end, we investigated the kinetics of the proliferation and apoptosis of donor T cells in recipient spleens in the early stage of a fully major histocompatibility complex (MHC)-mismatched murine transplantation model from C57BL/6 (H-2(b)) to lethally-irradiated (8.5 Gy) BALB/c (H-2(d)) mice. To track the behavior of alloreactive lymphocytes in vivo, we used the fluorescent cytoplasmic dye carboxyfluorescein diacetate succinimidyl ester in combination with flow cytometry. Engraftment of donor T cells to recipient spleens was almost completed within 24 h after transfer. After that, at higher doses of transferred cells, the donor T cells actively divided for up to 72 h resulting in a 30-fold increase in cell number at the maximum cell dose (2.0 x 10(7)). As the transferred cell dose decreased, the proliferation of T cells tended to be suppressed. At cell doses of 0.5 x 10(7) or less, the proliferation of T cells was profoundly suppressed, ultimately resulting in little proliferation of donor T cells observed from 24 to 72 h at the minimum cell dose (0.1 x 10(7)). The frequency of Annexin-V-positive cells was found to increase gradually as the transferred cell dose decreased. Thus, an increase in apoptotic events appeared to play an important role in the suppression of the proliferation of T cells at lower splenocyte doses. Further analyses revealed that Fas ligand (FasL)-positive T cells were observed exclusively among T cells that divided at least 5 times, and that all of them were positive for Annexin-V, indicating that they were in the process of apoptosis. Together with our finding that the frequency of apoptosis increased with the progression of cell division, these findings strongly suggest that AICD occurred through the Fas/FasL system and that AICD increased as the dose of donor T cells participating in the allogeneic response decreased. When relatively small numbers of T cells are confronted with an excess of antigen, they disappear. This process is called clonal exhaustion-deletion. Our results support the idea that AICD is involved in the process of clonal exhaustion-deletion. Relevant to the clinical aspects of hematopoietic cell transplantation, our findings indicate that AICD may be associated with tolerance induction in T-cell-depleted transplantation from HLA-mismatched donors, in which T cells contaminating marrow grafts do not need to be completely removed for achieving tolerance between donors and recipients. Furthermore, our results indicate that a small change in the quantitative balance between antigens and T cells responding to them leads to a large difference in the fate of T cells activated in response to MHC-incompatible antigens. Thus, the size of the T cell dose is one of the important considerations in tolerance induction, GVHD and rejection.
Adoptive Transfer↗