Identify Performing Candidates for Immunology Drug Discovery

Human Cells are Readily Accepted by Zebrafish:

Noémie Hamilton et al., published in 2018 that when human CD34 cells are injected into zebrafish, during the first hour they appeared to adhere to the endothelial wall of the blood vessels forming the Caudal Hematopoietic Tissue. At 9 hours post transplantation, co-localization of human CD34 cells with zebrafish endothelial cells, inside the perivascular pockets was observed termed ‘cuddling’; zebrafish endothelial cells surround and embrace the incoming human stem cell. The group concluded that human CD34 cells home into the zebrafish where they engage with endothelial cells. This is fundamental to understanding that human cells are readily accepted by zebrafish. This observation also draws parallel with that of observed xenotransplanted human cells into zebrafish where a minimal local inflammation may be observed for 48 hours, post after which the human cells are fully accepted into the zebrafish system.

If zebrafish system can accept and employ a functional human cell, how can the fish be employed for Pre-Clinical Development?

It appears that “almost all forms of human inflammatory pathology processes can be replicated in zebrafish carrying human cells - with reference to increasing evidence, from selected publications below

“Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and results in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells”

Jason N. Berman et al., 2020

“Human cells migrated within multiple tissues at speeds comparable to zebrafish macrophages. Gene expression analysis of in vivo educated human macrophages revealed gene expression associated with activation"

Kandice Tanner et al., 2019

“This procedure allows mammalian cell integration into the fish developmental hematopoietic program, which results in chimeric animals containing distinct phenotypes of murine blood cells in both circulation and the hematopoietic niche. Murine cells in chimeric animals’ express antigens related to (i) hematopoietic stem and progenitor cells, (ii) active cell proliferation and (iii) myeloid cell lineages"

Miguel L Allende et al., 2018

“Human HSCs home into the zebrafish haematopoietic niche, where they engage with endothelial cells and undergo cell division. Our model offers the opportunities to image in vivo human HSC engraftment in a transparent organism, without the myeloablative strategies used in mice, and provides a unique system to understand the dynamic process of engraftment and replace current murine models”

Noémie Hamilton et al., 2018

With the established prkdc−/−, il2rga−/− zebrafish and the further development of new immunodeficient zebrafish models, we envision the widespread application of immune compromised zebrafish for the study of cancer biology, stem cell and regenerative biology, and assessing therapy responses in vivo”

David M. Langenau et al., 2019

A full spectrum of candidate activity could be assessed in zebrafish model carrying human immune cells within 3-4 weeks.

Smear from zebrafish carrying human WBCs showing co-localization of human (larger cells) and zebrafish cells with no indications of adverse response.