Brain-spleen axis in health and diseases: A review and future perspective

Splenic stromal niches in homeostasis and immunity.

The development of safe and effective combination antiretroviral therapies for human immunodeficiency virus (HIV) infection over the past several decades has significantly reduced HIV-associated morbidity and mortality. Additionally, antiretroviral drugs have provided an effective means of protection against HIV transmission. Despite these advances, significant limitations exist; namely, the inability to eliminate HIV reservoirs, the inability to reverse lymphoid tissues damage, and the lack of an effective vaccine for preventing HIV transmission. Evaluation of the safety and efficacy of therapeutics and vaccines for eliminating HIV reservoirs and preventing HIV transmission requires robust in vivo models. Since HIV is a human-specific pathogen, that targets hematopoietic lineage cells and lymphoid tissues, in vivo animal models for HIV-host interactions require incorporation of human hematopoietic lineage cells and lymphoid tissues. In this review, we will discuss the construction of mouse models with human lymphoid tissues and/or hematopoietic lineage cells, termed, human immune system (HIS)-humanized mice. These HIS-humanized mouse models can support the development of functional human innate and adaptive immune cells, along with primary (thymus) and secondary (spleen) lymphoid tissues. We will discuss applications of HIS-humanized mouse models in evaluating the safety and efficacy of therapeutics against HIV reservoirs and associated immunopathology, and delineate the human immune response elicited by candidate HIV vaccines. In addition to focusing on how these HIS-humanized mouse models have already furthered our understanding of HIV and contributed to HIV therapeutics development, we discuss how emerging HIS-humanized rat models could address the limitations of HIS-mouse models.

https://link.springer.com/content/pdf/10.1186/s12977-020-00515-3.pdf

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies.

The human skin is a significant barrier for protection against pathogen transmission. Rodent models used to investigate human-specific pathogens that target the skin are generated by introducing human skin grafts to immunocompromised rodent strains. Infection-induced immunopathogenesis has been separately studied in humanized rodent models developed with human lymphoid tissue and hematopoietic stem cell transplants. Successful co-engraftment of human skin, autologous lymphoid tissues, and autologous immune cells in a rodent model has not yet been achieved, though it could provide a means of studying the human immune response to infection in the human skin. Here, we introduce the human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rγnull (NSG) mouse and Sprague–Dawley-Rag2tm2hera Il2rγtm1hera (SRG) rat models, co-engrafted with human full-thickness fetal skin, autologous fetal lymphoid tissues, and autologous fetal liver-derived hematopoietic stem cells. hSIS-humanized rodents demonstrate the development of human full-thickness skin, along with autologous lymphoid tissues, and autologous immune cells. These models also support human skin infection following intradermal inoculation with community-associated methicillin-resistant Staphylococcus aureus. The co-engraftment of these human skin and immune system components into a single humanized rodent model could provide a platform for studying human skin infections.

/pdf/development-of-humanized-mouse-and-rat-models-with-full-3vossmvnpl.pdf

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

Tetrastigma hemsleyanum Diels et Gilg is a traditional Chinese herbal medicine with high medicinal value, and antitumor, antioxidant and anti-inflammatory biological activities. However, while several studies have focused on flavonoids in Tetrastigma hemsleyanum tubers, there are few studies on the enhanced immune effect of Tetrastigma hemsleyanum polysaccharides (THP). In this study, we evaluated the antitumor effect of THP in a lung tumor model and explored the mechanism of antitumor activity through intestinal flora. In addition, a cyclophosphamide (CTX)-induced immunosuppression model was used to declare the immunomodulatory effect of THP in the immunosuppressive state induced by antitumor drugs. The results showed that THP increased the content of ileum secreted immunoglobulin A (SIgA) and cecum short-chain fatty acids (SCFAs) and improved microbial community diversity, regulating the relative abundance of dominant microbiota flora from the phylum level to the genus level, and recovering the intestinal microflora disorder caused by tumors. Additionally, THP can increase the organ indices and improve immune organ atrophy. THP can upregulate routine blood counts and stimulate the production of the serum cytokines. THP also promoted the macrophage phagocytic index, NK-cell activation, and complement and immunoglobulin (IgG, IgA, IgM) levels. The detection of Splenic lymphocyte proliferation and T lymphocyte subsets also sideways reflects that THP can restore CTX-induced immune inhibition in mice. In conclusion, this study suggests that THP can effectively achieve the enhanced antitumor effects, regulate gut microbiota and improve the immunosuppression induced by antitumor drugs. Therefore, THP can enhance the immune capacity and provide novel immunomodulatory and antineoplastic adjuvant agents. Graphical Abstract Mechanism of the antitumor and immunomodulatory action of THP. THP exerts an antitumor role by regulating intestinal flora. Meanwhile, THP plays an immunomodulatory role through specific immunity, nonspecific immunity and the intestinal tract. Created with BioRender.com.

/pdf/antitumor-effects-of-polysaccharides-from-tetrastigma-2zt86o6f.pdf

Antitumor effects of polysaccharides from Tetrastigma hemsleyanum Diels et Gilg via regulation of intestinal flora and enhancing immunomodulatory effects in vivo

A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation. Said model will enable in vivo mechanistic studies, thus complementing the well-established surrogate model of SIV infection-induced lymphoid tissue fibrosis in macaques. We developed a potentially novel human immune system-humanized mouse model by coengrafting autologous fetal thymus, spleen, and liver organoids under the kidney capsule, along with i.v. injection of autologous fetal liver-derived hematopoietic stem cells, thus termed the BM-liver-thymus-spleen (BLTS) humanized mouse model. BLTS humanized mouse model supports development of human immune cells and human lymphoid organoids (human thymus and spleen organoids). HIV infection in BLTS humanized mice results in progressive fibrosis in human lymphoid tissues, which was associated with immunodeficiency in the lymphoid tissues, and lymphoid tissue fibrosis persists during ART, thus recapitulating clinical outcomes.

/pdf/human-immunodeficiency-virus-infection-induces-lymphoid-4f5dna9vjn.pdf

Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model

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Human immunodeficiency virus infection induces lymphoid fibrosis in the BM-liver-thymus-spleen humanized mouse model