Table 3.

Animal models for CRS; description of two various models and the most important observations [25,27].

Giavridis et al. [25]	Norelli et al. [27]
Design of the model
Immunocompromised mice Intraperitoneal injection of Burkitt lymphoma Rajiv cells and NALM-6 pre-B ALL cells; mice were tested when vascularized tumors had developed intraperitoneally. CD18 recognizing CAR-T cells (human 1928 CAR-T cells)	Immunocompromised mice Human cord blood hematopoietic stem and progenitor cells were injected into the liver to reconstitute human hematopoiesis and development of immunocompetent cells. T cells from the mice were reconstituted with anti-CD44w6 or CD1920z CARs. THP1 and BV173 cells were used, in addition they used an ALL-CML cell line derived from a patient with CML in lymphoid blast phase and transfected with CD44 isoforms. These malignant cells were infused intravenously.
Local cellular responses
CAR-T cell recognition of the malignant cells Tumor infiltration of myeloid cells	CAR-T cells had antileukemic effects; recognized the specific CD44 isoform and had a durable antileukemic effect.
Systemic inflammatory markers
The systemic cytokine profile was very similar to patient CRS, including increased levels of the murine CRP equivalent; G-CSF, GM-CSF, IFN-γ, IL-2, IL-3, and IL-6	The mice developed a broad cytokine response, including increased levels of a murine CRP analogue as well as IL1, IL-6, IL-10, and TNF-α.
The role of monocytes
Host monocytes were a main source of released cytokines Monocytes express CD40 receptors, expression of CD40 ligand by CAR-T cells increased the severity of CRS CD40 ligation also increased the cytokine release by host monocytes. Expression of nitric oxide synthase was increased; aberrant nitric oxide production seemed to be directly involved in CRS pathophysiology probably due to its endothelial and/or vascular effects.	Monocytes were a major source of both IL-1 and IL-6. The monocytes expressed high levels of IL-1, IL-6, IL-8/CXCL8, CCL2, CCL8, and CXCL10. Dendritic cells also contributed to cytokine production.
Effects of therapeutic interventions
IL-1RA protected against CRS mortality	IL-1RA/akinera protected from lethal neurotoxicity, this was a unique effect. Tocilizumab also reduced CRS mortality. CRS treatment did not influence the antileukemic effect of CAR-T cells.