Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk.
Copyright © 2020 Yong, Her, Tan, Tan, Liu, Lai, Heng, Fan, Chang, Wang, Chan, Chen and Chen.

Several HIV-1 and SIV vaccine candidates have shown partial protection against viral challenges in rhesus macaques. However, the protective efficacy of vaccine-elicited polyclonal antibodies has not previously been demonstrated in adoptive transfer studies in nonhuman primates. In this study, we show that passive transfer of purified antibodies from vaccinated macaques can protect naive animals against SIVmac251 challenges. We vaccinated 30 rhesus macaques with Ad26-SIV Env/Gag/Pol and SIV Env gp140 protein vaccines and assessed the induction of antibody responses and a putative protective signature. This signature included multiple antibody functions and correlated with upregulation of interferon pathways in vaccinated animals. Adoptive transfer of purified immunoglobulin G (IgG) from the vaccinated animals with the most robust protective signatures provided partial protection against SIVmac251 challenges in naive recipient rhesus macaques. These data demonstrate the protective efficacy of purified vaccine-elicited antiviral antibodies in this model, even in the absence of virus neutralization.
Copyright © 2020 Elsevier Inc. All rights reserved.

Recent guidelines recommend antiretroviral therapy (ART) to be administered as early as possible during HIV-1 infection. Few studies addressed the immunological benefit of commencing ART during the acute phase of infection. We used mass cytometry to characterize blood CD4+ T cells from HIV-1-infected patients who initiated ART during acute or chronic phase of infection. Using this method, we analyzed a large number of markers on millions of individual immune cells. The results revealed that CD4+ T cell clusters with high expression of CD27, CD28, CD127, and CD44, whose function involves T cell migration to inflamed tissues and survival, are more abundant in healthy controls and patients initiating ART during the acute phase; on the contrary, CD4+ T cell clusters in patients initiating ART during the chronic phase had reduced expression of these markers. The results are suggestive of a better preserved immune function in HIV-1-infected patients initiating ART during acute infection.

The regulatory function of CCR7+CD8+ T cells against effector T-cells involved in T-cell mediated rejection (TCMR) in kidney transplant recipients was investigated. In vitro experiments explored the ability of CCR7+CD8+ T cells to suppress T-cell proliferation under T-cell activation conditions or during coculture with human renal proximal tubular epithelial cells (HRPTEpiC). In an ex vivo experiment, the proportion of CCR7+/CD8+, FOXP3+/CCR7+CD8+ T and effector T-cell subsets were compared between the normal biopsy control (NC, n = 17) and TCMR group (n = 17). The CCR7+CD8+ T cells significantly suppressed the proliferation of CD4+ T cells and significantly decreased the proportion of IFN-γ+ and IL-17+/CD4+ T cells and inflammatory cytokine levels (all p < 0.05). After coculturing with HRPTEpiC, CCR7+CD8+ T cells also suppressed T-cell differentiation into IL-2+, IFN-γ+, and IL-17+/CD4+ T cells (all p < 0.05). The TCMR group had significantly fewer CCR7+/CD8+ and FOXP3+/CCR7+CD8+ T in comparison with the NC group, but the proportions of all three effector T-cell subsets were increased in the TCMR group (all p < 0.05). The proportion of CCR7+/CD8+ T was inversely correlated with those of effector T-cell subsets. The results indicate that CCR7+CD8+ T cells may regulate effector T-cells involved in TCMR in an in vitro and in an ex vivo transplant model.

Dendritic cells (DC) are a promising cell type for cancer vaccines due to their high immunostimulatory capacity. However, improper maturation of DC prior to treatment may account for the limited efficacy of DC vaccine clinical trials. Latent Membrane Protein-1 (LMP1) of Epstein-Barr virus was examined for its ability to mature and activate DC as a gene-based molecular adjuvant for DC vaccines. DC were transduced with an adenovirus 5 vector (Ad5) expressing LMP1 under the control of a Tet-inducible promoter. Ad5-LMP1 was found to mature and activate both human and mouse DC. LMP1 enhanced in vitro migration of DC toward CCL19, as well as in vivo migration of DC to the inguinal lymph nodes of mice following intradermal injection. LMP1-transduced DC increased T cell proliferation in a Pmel-1 adoptive transfer model and enhanced survival in B16-F10 melanoma models. LMP1-DC also enhanced protection in a vaccinia-Gag viral challenge assay. LMP1 induced high levels of IL-12p70 secretion in mouse DC when compared to standard maturation protocols. Importantly, LMP1-transduced human DC retained the capacity to secrete IL-12p70 and TNF in response to DC restimulation. In contrast, DC matured with Monocyte Conditioned Media-Mimic cocktail (Mimic) were impaired in IL-12p70 secretion following restimulation. Overall, LMP1 matured and activated DC, induced migration to the lymph node, and generated high levels of IL-12p70 in a murine model. We propose LMP1 as a promising molecular adjuvant for DC vaccines.