Annual Meeting of the Japanese Society of Toxicology

Spermatozoa do not appear in the seminiferous epithelium until puberty, when immune tolerance already has been established. Therefore, they contain various autoimmunogenic materials which are recognized as foreign by the self-immune system. However, the testis is known as immunologically privileged organs. In particular, the blood–testis barrier (BTB) formed by Sertoli cells protect autoimmunogeneic spermatozoa from attack by the self-immune system. The immune privileged circumstances in the testis has been demonstrated by many studies to involve a local transplantation system. The testicular interstitium in mice is resistant to vasculitis, lymphangitis, spermatic granuloma and polymorphonuclear cell infiltration. Therefore, the testicular tissue outside BTB is also protected from inflammatory cell infiltration, although many resident macrophages are normally present in the testis. In sharp contrast, subcutaneous injection of viable syngeneic testicular germ cells (TGC) alone induces experimental autoimmune orchitis (EAO) in mice. In the testes of TGC-immunized animals, severe lymphocytic infiltration with aspermatogenesis was seen in spite of no use of adjuvants. Moreover, cadmium chloride (CdCl₂) and di-(2-ethylhexyl) phthalate (DEHP) as environmental toxicants is known to affects the immune system by acting as an adjuvant, recently, it also became evident that exposure to a low-dose of them affect the testicular immune-system. In this meeting, we show the immune privileged status of these organs from the viewpoint of induction of immune-responses induced by EAO and environmental toxicants.

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After many years of trying to harness the immune system to fight cancer, recent approvals of ipilimumab and nivolumab, as well as encouraging data emerging from clinical trials, are transforming the way cancer is being treated. However, despite amazing clinical responses, stimulating the immune system either by taking the breaks off of immune inhibitory pathways (ie, anti-CTLA4 or -PD1 antagonists) or hitting the gas with immunostimulatory pathways (anti-CD137 or CD40 agonists) has led to immune-related adverse events (irAEs) in the clinic, which can be serious or fatal. These irAEs are related to the mechanism of action of these agents, resulting in T-cell inflammatory infiltrations in tissues and increases in systemic inflammatory cytokines. This presentation reviews the nonclinical safety assessment for ipilimumab (Yervoy) a fully human monoclonal antibody inhibitor of CTLA4 (CD152), a receptor expressed on T-cells following activation. Ipilimumab potentiates T cell responses by blocking the inhibitory modulation of T-cell activation promoted by the interaction of CTLA4 with CD80/86 on antigen presenting cells. The unique challenges with regards to monitoring for immune stimulation and its potential to induce adverse consequences in the nonclinical studies conducted in monkeys and with human tissues/cells in vitro and their translation to the clinic will be discussed.

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Autoimmunity results from interactions of genetic factors and environmental factors, which include a variety of components such as infection, xenobiotics (drug, chemicals, vaccine, food, etc), geo-climate factors and others.
The mechanisms on how environmental factors trigger autoimmunity are heterogeneous and incompletely understood, however, non-specific immune stimulation (adjuvant effects) of xenobiotics may increase the risk to develop autoimmunity. Most vaccines contain adjuvants in addition to microbial components, to enhance immune responses, which may also trigger autoimmunity. A single intraperitoneal (ip) injection of an adjuvant oil pristane, a component of mineral oil, induces a type-I interferon and TLR7-dependent lupus-like autoimmune syndrome in mice. Ip injection of incomplete Freund’s adjuvant (mineral oil) and squalene (a main component of MF59 adjuvant used in human vaccines) also induced lupus autoantibodies. Mineral oils are generally considered inert, however, they also can induce arthritis in animals. Human exposure to mineral oils at work environment was associated with an increased risk to develop rheumatoid arthritis. Injection of mineral oil as a cosmetic procedure is common in Mexico, however, development of an autoimmune syndrome induced by adjuvants (ASIA) is reported. These patients had rheumatologic symptoms and antinuclear antibodies, anti-U1RNP, and -Su/Argonaute2, similar to animal models of mineral oil-induced autoimmunity.
For certain chemicals/drugs, induction of autoantibodies to the target molecule of the chemical/drug is shown. Mercury exposure induces anti-nucleolar antibodies that recognize a mercury-binding protein fibrillarin(U3RNP) in mice and human. Ribavirin used in hepatitis C viral infection induced autoantibodies to cytoplasmic rods and rings structure, which recognize the target molecule of the ribavirin, inosine monophosphate dehydrogenase (IMPDH).
Adjuvants and certain xenobiotics may induce autoimmunity via non-specific activation of the immune system but also by modifying specific antigens.

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The US Centers for Disease Control estimate that approximately 1.2 million US citizens are infected with HIV. Research shows the prevalence of cannabis use to be between 25 and 37% by HIV patients. Cannabinoids, including Δ⁹-tetrahydrocannabinol (THC), the major psychoactive constituent in cannabis, are well-established immune modulators. The impact of cannabis use by HIV patients on immune competence is poorly understood. The objective of the present study was to determine whether THC impairs Interferon alpha (IFNα) production by plasmacytoid dendritic cells (pDCs) and if so, the putative downstream effect on T cell function, including IL-7Rα expression. IFNα release is critical in the anti-viral host defense by exerting a broad spectrum of activity including promoting T cell responsiveness and expansion, in part, through up-regulation of IL-7Rα on T cells. Human pDCs from HIV^- or HIV⁺ donors were strongly induced by CpG-ODN to secrete IFNα and suppressed by THC. Quantitative PCR confirmed cannabinoid receptor (CBR) 1 and 2 expression by pDC. THC treatment decreased the percentage of pDC expressing the critical SLAM receptor adaptor protein, EAT-2, providing insights into THC-mediated IFNα suppression. T cells demonstrated an elevation of surface IL-7Rα following IFNα treatment, which was significantly attenuated by THC. Interestingly, CD4⁺ and CD8⁺ T cells from HIV⁺ donors were more responsive to IFNα, as measured by IL7Rα up-regulation, than from HIV^- donors. These studies show that THC suppressed pDC-derived IFNα release in HIV^- and HIV⁺ donors, with impairment of IL-7Rα responsiveness to IL-7 stimulation.

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