The hIL-2 NOG mouse as a preclinical model for psoriasis

Psoriasis is an autoimmune disease that affects 2-3% of the global population, and its onset can be triggered by stimuli such as streptococcal infection of the upper respiratory tract, stress, sunburn, and even medications such as β blockers, lithium, and antimalarials¹. Furthermore, it presents as an inflammatory skin condition characterized by T cell-mediated hyperproliferation of keratinocytes with clinical phenotypes including plaque lesions, acute and usually self-limiting guttate type eruptions, seborrheic psoriasis, pustular lesions, and at least 10% of psoriasis patients develop arthritis². Various triggers that prompt psoriasis can result in the generation of interleukin (IL) -23, a cytokine that stimulates the production of several other cytokines, including IL-17. These cytokines, whether directly or indirectly, subsequently alter the function of keratinocytes and other cells within the skin tissue¹.

While there is no animal model that precisely replicates the complex characteristics of psoriasis, extensive research involving spontaneous or genetically modified mutations in rodents, immunological reconstitution techniques, and xenotransplantation models have provided insights that can help elucidate some of its pathophysiology and treatment. Additionally, animal models have played a crucial role in revealing the functions of inflammatory mediators and providing valuable insights into the participation of innate and adaptive immune processes, keratinocytes, and endothelial cells in chronic hyperproliferative inflammatory skin conditions³. A recent study published in PLOS ONE highlights Taconic`s hIL-2 NOG mouse as a potential model to study psoriasis⁴.  This model expresses the human cytokine IL-2, a critical factor in the activation and upkeep of T cells^5,6. 

A preclinical mouse model for psoriasis

The widespread systemic presence of human T cells triggered Graft versus Host Disease (GvHD), which imposed limitations on the study's duration. These histocompatibility differences emerge when immunocompetent T lymphocytes in the graft attack the immunodeficient host¹⁰. Nevertheless, the hIL-2 NOG provides valuable benefits as a host such as promoting T cell proliferation within grafts and aiding their migration into the bloodstream. This is crucial for studying psoriasis. Hence, additional research on graft sources is necessary to ascertain that the onset of GvHD can vary based on the donor.

Human T cell Activity 

To assess T cell activity within grafts and serum, the researchers examined disease-relevant cytokines such as IL-17 A, IL-22, IFNγ, and TNFα. In comparison to C.B-17 and NOG mice, all these cytokines exhibited higher levels in hIL-2 NOG mice. The activity of T cells, as evidenced by the presence of these cytokines, remained stable in hIL-2 NOG mice for a minimum of two weeks and gradually decreased within the grafts over time. The presence of IL-23/IL-17 pathway is critical for psoriasis models, and because of the sustained levels of human IL-17A in grafts from hIL-2 NOG mice 15 days after engraftment, the authors hypothesized that the IL-23/IL-17 pathway was present. After assessing the efficacy of ustekinumab, a monoclonal antibody (IgG1κ) targeting the shared p40 subunit of IL-12 and IL-23, there were no notable variations in the protein levels of human IL-17A, IL-22, IFN-γ, and TNF-α in grafts from mice treated with ustekinumab compared to those treated with isotype controls. This implies that the ineffectiveness might be attributed to IL-23 not being responsible for inducing the production of human IL-17A.

Conclusion

Though the hIL-2 NOG model is indeed valuable for investigating psoriasis, it is crucial to acknowledge that this model can develop GvHD, leading to a shortened study period of 3 weeks compared to 7-8 weeks in the NOG. This phenomenon may be attributed to elevated levels of CD8+ T cells, a characteristic feature of GvHD¹¹. Due to the limited study duration imposed by GvHD, this model does not permit the assessment of epidermal thickness. Nonetheless, the study demonstrated the persistence of T cell activity in grafts when lesioned human psoriasis skin was transplanted onto the hIL-2 NOG, mimicking the systemic nature of psoriasis¹². This enables the exploration of treatments for psoriasis at both local and systemic levels. Further research is needed to understand the role of GvHD in immune activity and to characterize the cellular infiltration of grafts while improving skin appearance.

In summary, while not all aspects of psoriasis can be entirely replicated in the hIL-2 NOG, this study demonstrates that transplanting psoriasis skin onto human IL-2 NOG mice enhances the presence of human T cells and elevates disease-relevant cytokine levels. Additional research and validation are necessary to fully grasp the intricacies of psoriasis within this model for the purposes of drug development and research.

References:

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