Anti-IL-2 Antibody [MT2A91 + 2C95] (A269868)

In this study, we sought out to study the anti-cancer effects of propranolol (Pro) in combination with tumor lysate vaccine on lymphocyte proliferation activities as well as on IL-2, IL-4, IL-10, IL-12, IL-17 and IFN-? cytokine concentration in the tumor microenvironment (TME). A tumor model was established in inbred Balb/C mice using transplantation of tumor to the flank of native mice. Tumor-bearing mice were immunized with lysate tumor cells (vaccine), a combination of Pro/Vaccine (Vac). Control groups consisted of tumor-bearing mice receiving only propranolol or PBS three times with one week interval via subcutaneous (s.c) injection. One week after the last immunization, tumor was removed, homogenate was prepared and the levels of IL-12, IL-17, 1L-2, IL-10, IL-4, IFN-? cytokine concentrations were evaluated by commercial ELISA kits. In addition, spleen cell suspension was used for the lymphocyte proliferation assay using the BrdU method. Results from this study indicated that Pro/Vac had the ability to significantly increase lymphocyte proliferation, and to suppress tumor growth. Administration of breast tumor lysates with propranolol increased the concentration of IL-12, IL-17, 1L-2 and IFN-? cytokines in tumor microenvironment. This study has proved the efficiency of propranolol as an adjuvant in combination with the tumor vaccine model on tumor suppression via cytokine pattern modulation in tumor microenvironment.

Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation. The majority of CTLA4 molecules showing the largest potency gains in primary in vitro and ex vivo human cell assays, using PBMCs from type 1 diabetes patients, had significant improvements in CD80, but only modest gains in CD86 binding. We furthermore observed different potency rankings between our lead molecule MEDI5265, abatacept, and belatacept, depending on which type of APC was used, with MEDI5265 consistently being the most potent. We then created fusions of both stability- and potency-optimized CTLA4 moieties with human Fc variants conferring extended plasma t_1/2 In a cynomolgus model of T cell-dependent Ab response, the CTLA4-Ig variant MEDI5265 could be formulated at >100 mg/ml for s.c. administration and showed superior efficacy and significantly prolonged serum t_1/2 The combination of higher stability and potency with prolonged pharmacokinetics could be compatible with very infrequent, s.c. dosing while maintaining a similar level of immune suppression to more frequently and i.v. administered licensed therapies.

Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively analysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61·5%) and 187 (38·5%) cases, respectively. Of note, seven of the 111 (6·3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reactive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV-6B reactivation and chronic/recurrent benign lymphadenopathy.

Chronic immune activation is a hallmark of HIV-1 infection; specifically, the activation of T cells has predictive value for progression to AIDS. The majority of hyperactivated T cells are not HIV-specific and their antigenic specificities remain poorly understood. Translocation of gut luminal microbial products to systemic sites contributes to chronic immune activation during HIV-1 infection, but how it affects (TCR-dependent) immune activation remains elusive. We hypothesized that gut luminal antigens foster activation of CD4(+) T cells with specificities for commensal bacterial antigens, thereby contributing to the pool of activated CD4(+) T cells in the circulation of HIV-1 infected individuals. To test this hypothesis, we quantified the frequencies of gut microbe-specific CD4(+) T cells by cytokine production upon restimulation with selected gut commensal microbial antigens. Contrary to our hypothesis, we did not observe increased but rather decreased frequencies of gut microbe-specific CD4(+) T cells in HIV-1 infected individuals compared to healthy controls. We conclude that the increased activation status of circulating CD4(+) T cells in HIV-1 infected individuals is not driven by CD4(+) T cells with specificities for commensal bacterial antigens.

Background: Although antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood.

Methodology/principal findings: Using ex vivo IFN? ELISpot assays, and by determining cytokines produced in ELISpot supernatants, we investigated the functionality of DENV-specific memory T cell responses in a large cohort of individuals from Sri Lanka (n=338), who were naturally infected and were either hospitalized due to dengue or had mild or sub clinical dengue infection. We found that T cells of individuals with both past mild or sub clinical dengue infection and who were hospitalized produced multiple cytokines when stimulated with DENV-NS3 peptides. However, while DENV-NS3 specific T cells of those with mild/sub clinical dengue infection were more likely to produce only granzyme B (p=0.02), those who were hospitalized were more likely to produce both TNFa and IFN? (p=0.03) or TNFa alone. We have also investigated the usefulness of a novel T cell based assay, which can be used to determine the past infecting DENV serotype. 92.4% of DENV seropositive individuals responded to at least one DENV serotype of this assay and none of the seronegatives responded. Individuals who were seronegative, but had received the Japanese encephalitis vaccine too made no responses, suggesting that the peptides used in this assay did not cross react with the Japanese encephalitis virus.

Conclusions/significance: The types of cytokines produced by DENV-specific memory T cells appear to influence the outcome of clinical disease severity. The novel T cell based assay, is likely to be useful in determining the past infecting DENV serotype in immune-epidemiological studies and also in dengue vaccine trials.