Jinkyo Sakurai

Blockade of CTLA-4 Signals Inhibits Th2-Mediated Murine Chronic Graft-Versus-Host Disease by an Enhanced Expansion of Regulatory CD8+ T Cells

CTLA-4 (CD152) is thought to be a negative regulator of T cell activation. Little is known about the function of CTLA-4 in Th2-type immune responses. We have investigated the effect of initial treatment with anti-CTLA-4 mAb on murine chronic graft-vs-host disease. Transfer of parental BALB/c splenocytes into C57BL/6 × BALB/c F1 mice induced serum IgE production, IL-4 expression by donor CD4+ T cells, and host allo-Ag-specific IgG1 production at 6–9 wk after transfer. Treatment with anti-CTLA-4 mAb for the initial 2 wk significantly reduced IgE and IgG1 production and IL-4 expression. Analysis of the splenic phenotype revealed the enhancement of donor T cell expansion, especially within the CD8 subset, and the elimination of host cells early after anti-CTLA-4 mAb treatment. This treatment did not affect early IFN-γ expression by CD4+ and CD8+ T cells and anti-host cytolytic activity. Thus, blockade of CTLA-4 greatly enhanced CD8+ T cell expansion, and this may result in the regulation of consequent Th2-mediated humoral immune responses. These findings suggest a new approach for regulating IgE-mediated allergic immune responses by blockade of CTLA-4 during a critical period of Ag sensitization.

Preferential Blockade of CD8+ T Cell Responses by Administration of Anti-CD137 Ligand Monoclonal Antibody Results in Differential Effect on Development of Murine Acute and Chronic Graft-Versus-Host Diseases

We investigated the effect of CD137 costimulatory blockade in the development of murine acute and chronic graft-vs-host diseases (GVHD). The administration of anti-CD137 ligand (anti-CD137L) mAb at the time of GVHD induction ameliorated the lethality of acute GVHD, but enhanced IgE and anti-dsDNA IgG autoantibody production in chronic GVHD. The anti-CD137L mAb treatment efficiently inhibited donor CD8+ T cell expansion and IFN-γ expression by CD8+ T cells in both GVHD models and CD8+ T cell-mediated cytotoxicity against host-alloantigen in acute GVHD. However, a clear inhibition of donor CD4+ T cell expansion and activation has not been observed. On the contrary, in chronic GVHD, the number of CD4+ T cells producing IL-4 was enhanced by anti-CD137L mAb treatment. This suggests that the reduction of CD8+ T cells producing IFN-γ promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effective inactivation of CD8+ T cells and the lesser effect on CD4+ T cell inactivation by CD137 blockade. Intervention of the CD137 costimulatory pathway may be beneficial for some selected diseases in which CD8+ T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach will be required for intervention of CD4+ T cell function.

Long-term outcome of non-surgical treatment in patients with oral leukoplakia

UNLABELLED The standard treatments for oral leukoplakia range from careful observation to complete resection. No surgical intervention is chosen for several supposable reasons. Surgical treatment and no surgical treatment for oral leukoplakia have no defined basis for comparisons, and few studies have reported on the long-term outcomes of oral leukoplakia without surgery. OBJECTIVES This study aimed to identify the important factors using a long-term wait-and-see policy in patients with oral leukoplakia. MATERIALS AND METHODS In total, 237 lesions from 218 patients selected for non-surgical therapy between 2001 and 2010 were analyzed. On the basis of long-term follow-up data, lesions were classified as unchanged, reduced, disappeared, expanded, and malignantly transformed. RESULTS In total, 135 (57.0%) lesions remained unchanged, 30 (12.7%) lesions were characterized by a reduction in size or clinical severity, and 44 (18.6%) lesions had disappeared. Another 17 (7.2%) lesions resulted in spread or clinical deterioration, and 11 (4.6%) lesions developed oral squamous cell carcinoma. CONCLUSIONS We demonstrated a cumulative malignant transformation rate of 11.6% in 10years without resection. The lesions that were nonhomogeneous, and higher degree of epithelial dysplasia, located on the tongue were likely to progress into cancer. In addition, 32.5% of lesions without surgical treatment were reduced or disappeared. There is a possibility that removal of considerable irritation for a long time contributes to the treatment of this disease. The development of appropriate treatments for oral leukoplakia is required, which will enable successful differentiation between surgical and observation cases.