When rat models could provide optimized translatability: the case of CD89

Preclinical models’ relevance and physiology are of utmost importance to increase translatability. As far as rodent models go, mice have taken the No. 1spot, mainly for technical (and financial) reasons, mostly because genetic modifications are easier in mice than other rodents. However, the rat is now making a comeback, especially with the development of CRISPR technology. There are a number of reasons why rats may be preferred to mice, one being that the human gene of interest presents a homolog in the rat, but not in the mouse. This is the case for the IgA Fc receptor CD89, also known as FcαRI.

CD89 is a member of the Fc receptor immunoglobulin superfamily. Together with its ligand IgA, it is involved in host–pathogen defense. Indeed, CD89 binding by IgA complexes induces pro-inflammatory responses, leading to the elimination of pathogens. Additionally, CD89 may also play a role in maintaining homeostatic conditions. In humans, CD89 is expressed at the surface of myeloid cells such as neutrophils, monocytes, macrophages and eosinophils. Due to its role in mediating immunologic responses to pathogens, CD89 is a therapeutical target of interest for allergy and inflammation, but also cancer.¹ Relevant preclinical models humanized for this target thus represent useful tools for the study and development of therapeutics.

Interestingly, there is no CD89 homolog in the mouse. In this species, CD351 is the only receptor known to bind IgA. Mouse models have, nevertheless, been developed to express a human CD89.^2-4 Although these models proved very helpful for the study of IgA/CD89 binding mechanism of action and involvement in some pathologies, they all show either a phenotype2 or incomplete expression profile and function.^3-6 When looking for alternative models, the rat could be of particular interest, as a CD89 homolog was described in this species.⁷ Although CD89 expression is still poorly documented in rats (one RNA-Seq study suggests that it may be expressed, albeit at low levels, in the spleen and lung,⁸and its expression was confirmed in eosinophils⁹), it is a relevant alternative model to the “CD89-less” mouse.

As of today, there is no available CD89 rat model, but a knockout model has been developed and should be published soon.¹⁰ Considering the inherent characteristics of this species, genetic in this case, a humanized rat model could display optimized CD89 expression profile and function, thus providing improved translatability.

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References:

1. Breedveld A. & van Egmond M. IgA and FcαRI: Pathological Roles and Therapeutic Opportunities. Front Immunol. 2019 Mar 22;10:553. doi: 10.3389/fimmu.2019.00553.
2. Launay P., Grossetête B., Arcos-Fajardo M., et al. Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice. J Exp Med. 2000 Jun 5;191(11):1999-2009. doi: 10.1084/jem.191.11.1999.
3. van Egmond M., van Vuuren A.J., Morton H.C., et al. Human immunoglobulin A receptor (FcalphaRI, CD89) function in transgenic mice requires both FcR gamma chain and CR3 (CD11b/CD18). Blood. 1999 Jun 15;93(12):4387-94.
4. Xu L., Li B., Huang M., et al. Critical Role of Kupffer Cell CD89 Expression in Experimental IgA Nephropathy. PLoS One. 2016 Jul 20;11(7):e0159426. doi: 10.1371/journal.pone.0159426.
5. van Egmond M., van Garderen E., van Spriel A.B., et al. FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med. 2000 Jun;6(6):680-5. doi: 10.1038/76261.
6. Li B., Xu L., Pi C., et al. CD89-mediated recruitment of macrophages via a bispecific antibody enhances anti-tumor efficacy. Oncoimmunology. 2017 Oct 12;7(1):e1380142. doi: 10.1080/2162402X.2017.1380142.
7. Maruoka T., Nagata T., Kasahara M. Identification of the rat IgA Fc receptor encoded in the leukocyte receptor complex. Immunogenetics. 2004 Jan;55(10):712-6. doi: 10.1007/s00251-003-0626-1.
8. Yu Y., Fuscoe J.C., Zhao C., et al. A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages. Nat Commun. 2014;5:3230. doi: 10.1038/ncomms4230.
9. Decot V., Woerly G., Loyens M., et al. Heterogeneity of expression of IgA receptors by human, mouse, and rat eosinophils. J Immunol. 2005 Jan 15;174(2):628-35. doi: 10.4049/jimmunol.174.2.628.
10. Chenouard V., Remy S., Tesson L., et al. Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models. Front Genet. 2021 Apr 20;12:615491. doi: 10.3389/fgene.2021.615491.