Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases

Tahvildari, Maryam; Dana, Reza

doi:10.4049/jimmunol.1900733

Cited by 82 publications

(63 citation statements)

References 59 publications

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“…Although the synergistic capacity of CD4 + and CD8 + Tregs is not yet clear, both subsets could show complementary effects and it could be beneficial to administer them together to patients (24). IL-34 could also be used in vivo together with Treg cell therapy to promote the persistence and the function of the induced Tregs, as is done with low-dose IL-2 or rapamycin (52,53), by enrichment of the environment with tolerogenic macrophages and by direct action on Tregs. We have tested in vivo the FOXP3 + CD8 + Tregs induced in the 14-day ex vivo expansion in a model of xenogeneic GVHD in immune-humanized mice, and we have observed a similar protective potential of the Tregs compared to what we have previously demonstrated using polyclonally expanded CD8 + Tregs (14).…”

Section: Discussionmentioning

confidence: 99%

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

et al. 2020

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Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4 + and CD8 + FOXP3 + Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4 + and CD8 + FOXP3 + Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graftvs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4 + and CD8 + FOXP3 + Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8 + Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3 + Tregs.

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Section: Discussionmentioning

confidence: 99%

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

et al. 2020

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“…This representation of the cytokine modulation is shown with a promising approach in detail in the case of corneal transplantation by Reza Dana et al, using several animal models. They have shown the beneficial effects of low-dose IL-2 and IL-6 blocking antibody in their previous papers ( 69 , 70 ). Secondly, after understanding of the involvement of the cytokines in several conditions of the diseases, one can predict/design a drug, using one cytokine or combination of the cytokines.…”

Section: Conclusion and Discussionmentioning

confidence: 93%

Cluster Analysis of Dry Eye Disease Models Based on Immune Cell Parameters – New Insight Into Therapeutic Perspective

2020

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Dry eye disease (DED) can be represented as a display of disease in the mucosal part of the eye. It is quite distinct from the retinal side of the eye which connects with the neurons and thus represents the neuroimmunological disease. DED can occur either by the internal damage of the T cells inside the body or by microbial infections. Here we summarize the most common animal model systems used for DED relating to immune factors. We aimed to identify the most important immune cell/cytokine among the animal models of the disease. We also show the essential immune factors which are being tested for DED treatment. In our results, both the mechanism and the treatment of its animal models indicate the involvement of Th1 cells and the pro-inflammatory cytokine (IL-1β and TNF-α) related to the Th1-cells. The study is intended to increase the knowledge of the animal models in the field of the ocular surface along with the opening of a dimension of thoughts while designing a new animal model or treatment paradigm for ocular surface inflammatory disorders.

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“…At lower doses, IL-2 activates and expands Tregs and has been investigated in several proof-of-concept, dose-finding, and phase 1/2 trials in vasculitis, refractory GVHD, type 1 diabetes, alopecia, and systemic lupus erythematosus. 7 In general, IL-2 was well tolerated, and an increase in Tregs was noted in most studies. Clinical benefit was observed; however, given the lack of a control group, IL-2's activity could not be determined.…”

mentioning

confidence: 89%

“…In combination with CsA, the Treg activity of low-dose IL-2 could be negatively affected. 7 In combination with agents that result in profound and prolonged lymphopenia (eg, rabbit ATG and alemtuzumab), the increase in Treg frequency provided by IL-2 could be curtailed by the absolute reduction in lymphocytes. Thus, the development of IL-2 would need to be well strategized in AA.…”

mentioning

confidence: 99%