Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches

Abstract

Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

“…However, the deficient immune systems of NSG and NOG mice preclude observing changes in the immune system [49] , the interaction of immune cells and tumor cells, and, importantly, the influences of CAR-NK or CAR-T therapy on host immune cells in the tumor microenvironment. Humanized mice, which develop a functional human immune system due to the transplantation of human hematopoietic stem cells into immunodeficient mice, are used to narrow the gap of the tumor microenvironment [50] .…”

hESC-derived photoreceptors survive and integrate better in immunodeficient retina

“…One word of caution: Zhu et al argued that immunosuppression may have enhanced transplant integration in the study of Shirai et al (5), but this study already used cyclosporine A as immunosuppressant. The study by Zhu et al confirms that immunodeficient animal models are better for transplant survival and integration than models that need immunosuppression by drugs because of the side effects of immunosuppressant drugs (24). It is unclear however, how this would translate to future clinical trials.…”

“…The side effects of immunosuppressive drugs are difficult to balance against any visual benefits, in contrast to the benefits of immunosuppression for organ replacement (24).…”

Blocking CD226 Promotes Allogeneic Transplant Immune Tolerance and Improves Skin Graft Survival by Increasing the Frequency of Regulatory T Cells in a Murine Model

“…In the Isotype and anti-CD226 groups, 3 mg/kg/d Rapa (Calbiochem) was given intraperitoneally (i.p.) from days 0 to 10 [18]. Skin allografts were considered rejected if ≥ 70% of the surface was necrotic.…”