Prophylactic and Therapeutic Effects of Interleukin-2 (IL-2)/Anti-IL-2 Complexes in Systemic Lupus Erythematosus-Like Chronic Graft-Versus-Host Disease

Abstract

Murine chronic graft-versus-host-disease (cGvHD) induced by injection of parental lymphocytes into F1 hybrids results in a disease similar to systemic lupus erythematosus. Here, we have used DBA/2 T cell injection into (C57BL/6 × DBA/2)F1 (BDF1) mice as a model system to test the prophylactic and therapeutic effects of interleukin-2 (IL-2)/anti-IL-2 immune complexes on the course of cGvHD. Our findings demonstrate that pretreatment with Treg inducing JES6/IL-2 complexes render BDF1 mice largely resistant to induction of cGvHD, whereas pretreatment with CD8+ T cell/NK cell inducing S4B6/IL-2 complexes results in a more severe cGvHD. In contrast, treatment with JES6/IL-2 complexes 4 weeks after induction had no beneficial effect on disease symptoms. However, similar treatment with S4B6/IL-2 complexes led to a significant amelioration of the disease. This therapeutic effect seems to be mediated by donor CD8+ T cells. The fact that a much stronger cGvHD is induced in BDF1 mice depleted of donor CD8+ T cells strongly supports this conclusion. The contrasting effects of the two different IL-2 complexes are likely due to different mechanisms.

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

“…Though the cause of this contraction remains undefined, we find that prophylactic treatment of diseased mice with either IL-2C or N-803 can counteract NK-cell loss and even promote expansion of the NK-cell pool. Coupled with experiments detailing IL-2-based therapeutics in the MRL/lpr and B6 x DBA mouse models 28,29 , these data support the conclusion that therapeutic expansion of NK cells is possible in the context of lupus-like disease.…”

“…As a pre-disease treatment, each mixture was intraperitoneally injected every other day for a total of 3 injections, after which a bm12 splenocyte graft was injected the following day (see above). As a post-disease treatment, injections were administered once daily for three days beginning one month after graft injection 29 .…”

“…To assess whether therapeutic cytokine-mediated expansion of NK cells can alleviate established lupus-like disease, control and bm12-recipient mice were administered daily therapeutic regimens of IL-2C for 3 consecutive days starting one month after disease initiation, an approach that parallels a prior study using this complex in a similar disease model 29 . Two-months after therapy initiation, IL-2Ctreated mice exhibited increased host splenic plasmablast counts and elevated sera ANA titers relative to control treated mice (Figure 3).…”

“…Daclizumab-mediated expansion of immunoregulatory NK cells in multiple sclerosis patients is linked to clinical lessening of disease 26,27 , whereas IL-2C treatment reduced disease measures in the MRL/lpr mouse model of lupus 28 . Likewise, lupus-like disease in the B6 × DBA/2 F1 mouse model was alleviated by therapeutic administration of IL-2C 29 . In contrast, pre-treatment with IL-2C prior to disease initiation resulted in worse disease.…”

Effect of Tea Polyphenol on Serum Hormone, Serum Enzyme Activity and Antioxidant-Related Gene Expression in Chinese Yellow Chicken under Heat Stress

“…And it is a highly potent antiviral cytokine with broad-spectrum immunomodulatory effects [55]. It is reported that the beginning of IL-2 function depends on B and T lymphocytes, which is one of the most important lymphoid factors regulating the immune function of the body [56]. Similarly, the function of Th2 relies on the secretion of IL-4…”