No abstract

NRS1 is a murine squamous cell carcinoma that constitutively expresses the co-stimulatory molecule CD80 at a high level yet grows as a tumour in syngeneic C3H mice. We examined the effect of gene transfer of the 4-1BB ligand (4-1BBL) into NRS1 cells. Introduction of the 4-1BBL gene efficiently elicited anti-tumour immune responses in syngeneic mice which acquired specific immunity against wild-type tumour. T-cell depletion studies showed that CD8(+), but not CD4(+) T cells were essential for tumour eradication. Our results suggest that the transduced 4-1BBL is more effective than the spontaneously expressed CD80 for generation of primary anti-tumour CD8(+) T-cell responses. In addition to CD80 and CD86, the host-derived 4-1BBL is also involved in the secondary anti-tumour responses. This study indicates the complicated contribution of 4-1BBL, CD80 and CD86 on tumour and host cells in anti-tumour immune responses and a possible therapeutic application of 4-1BBL for human tumour vaccination and gene therapy.

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.

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.

Background Oral lichen planus (OLP) is a chronic inflammatory oral mucosa disease that is recognized as an oral potentially malignant disorder. However, the potentially malignant nature of OLP remains unclear. Methods We designed this study to examine the demographic and clinical characteristics of patients with OLP and evaluate the associated malignant transformation rate. A total of 565 patients with a clinical and histopathological diagnosis of OLP who presented at our department between 2001 and 2017 were retrospectively studied. Patients who had clinical and histopathological features of oral lichenoid lesions (OLLs) classified as oral lichenoid contact lesions, oral lichenoid drug reactions and oral lichenoid lesions of graft-versus-host disease were excluded. Results The study population included 123 men and 442 women aged 21–93 years (mean ± standard deviation, 60.5 ± 11.8). The 565 patients were followed up for a duration of 55.9 ± 45.3 months, during which 4 (0.7%) patients developed squamous cell carcinoma (SCC). In three of these 4 patients who developed SCC, the clinical type of OLP was the red type. Conclusions Our results suggested that OLP was associated with a low risk of malignant transformation. We recommend regular follow-up for OLP patients and clear differentiation of oral epithelial dysplasia and OLLs to enable early detection of malignant transformation. Further investigation of the clinical risk factors associated with malignant transformation is necessary.

An optimal T cell activation requires antigen stimulation and co-stimulation. CD28 and CD40 co-stimulation may play crucial roles in the interaction between T cells and antigen-presenting cells (APC). Blockade of either CD28 or CD40 pathway with MoAbs or recombinant fusion proteins (e.g. CTLA-4Ig) inhibits lethal acute graft-versus-host disease (GVHD) efficiently [1][2][3][4][5]. The simultaneous blockade of the CD28 and CD40 pathways successfully induces long-term acceptance of allografts [6][7][8], suggesting that a combined co-stimulatory signal blockade has a great promise for clinical application. However, in allogeneic bone marrow transplantation (BMT) for leukaemia treatment, the therapeutic requirement is not a complete immunosuppression but rather a moderate suppression with a preserved graftversus-leukaemia (GVL) effect.On the one hand, CD28 and CD40 are involved in antitumour immune responses. Transduction of CD154, CD80 or CD86 into leukaemia cells induces host antileukaemia responses mediated by T and NK cells [9][10][11][12][13]. Therefore, blockade of these molecules may reduce antileukaemia immune responses after BMT. On the other hand, Blazar et al. [14] demonstrated that the GVL effect against leukaemia cells in delayed lymphocyte infusion (DLI) post-BMT was eliminated by treatment with anti-CD80 MoAbs, suggesting involvement of the CD28-CD80 pathway in the GVL effect. The depletion of T cells from the bone marrow (BM) graft prevents GVHD, but increases the risk of leukaemia relapse, suggesting the involvement of donor T cells in both the GVH reaction and the GVL effect. Several recent reports demonstrated the differential effects between GVHD prophylaxis and the GVL effect by IL-2 [15], a metalloproteinase inhibitor [16], and IL-11 [17]. These observations suggested that the molecules and effector cells involved in the GVH reaction and the GVL effect are not completely identical.In this study, we have compared the effect on GVL of GVHD prophylaxis using either treatment with anti-CD154 MoAb or a combination of anti-CD80 and CD86 MoAbs in a murine model of fully major histocompatibility complex (MHC)-mismatched allogeneic BMT with a simultaneous injection of leukaemia cells. We further compared the effector function of T cells, NK cells and APC in the recipient mice after performing these two types of co-stimulatory blockades. 61Differential graft-versus-leukaemia effect by CD28 and CD40 co-stimulatory blockade after graft-versus-host disease prophylaxis SUMMARYCo-stimulatory blockade may be a promising strategy for tolerance induction in transplantation. In allogeneic bone marrow transplantation (BMT) for leukaemia treatment, however, preservation of the graft-versus-leukaemia (GVL) effect is another critical requirement for clinical application. In this study, we have compared the effect on GVL of using CD28 and CD40 co-stimulatory blockades as graft-versus-host disease (GVHD) prophylaxis in a murine allogeneic BMT model with simultaneous transfer of BCL1 leukaemia. Despite the relative imp...

NRS1 is a murine squamous cell carcinoma that constitutively expresses the co-stimulatory molecule CD80 at a high level yet grows as a tumour in syngeneic C3H mice. We examined the effect of gene transfer of the 4-1BB ligand (4-1BBL) into NRS1 cells. Introduction of the 4-1BBL gene efficiently elicited anti-tumour immune responses in syngeneic mice which acquired specific immunity against wild-type tumour. T-cell depletion studies showed that CD8(+), but not CD4(+) T cells were essential for tumour eradication. Our results suggest that the transduced 4-1BBL is more effective than the spontaneously expressed CD80 for generation of primary anti-tumour CD8(+) T-cell responses. In addition to CD80 and CD86, the host-derived 4-1BBL is also involved in the secondary anti-tumour responses. This study indicates the complicated contribution of 4-1BBL, CD80 and CD86 on tumour and host cells in anti-tumour immune responses and a possible therapeutic application of 4-1BBL for human tumour vaccination and gene therapy.

Oral squamous cell carcinoma (OSCC) is one of the most common solid tumours occurring after haematopoietic stem cell transplantation (HSCT), especially in patients with chronic graft-versus-host-disease (cGVHD). We describe a case of OSCC that developed in a 51-year-old male 22 years after he had received allogeneic HSCT from his human leukocyte antigen-identical sister as a treatment for acute myelocytic leukaemia. The patient had presented with multiple white patchy lesions on the palatal gingiva and mucosa 16 years after HSCT; these lesions were consistent with the clinical features of cGVHD. Six years later, oral examination and biopsy revealed upper gingival squamous cell carcinoma (SCC) in areas of cGVHD, and he underwent tumour excision. Follow-up examination at 2 years and 4 months after the operation revealed no evidence of recurrence of local SCC or metastasis of the cervical lymph node. The current case highlights the susceptibility of patients with cGVHD to the development of OSCC even two decades after HSCT. Therefore, we recommend careful long-term follow-up of the oral cavity for patients with cGVHD.