Role in allergies It has been shown that IL-21R knock-out mice express higher levels of IgE and lower levels of IgG1 than normal mice after antigen exposure. IgE levels decreased after mice were injected with IL-21. This has implications for the role of IL-21 in controlling allergic responses because of the role of IgE in hypersensitivity type 1 responses. IL-21 has been tried as therapy for alleviating allergic responses. It was shown to be successful in decreasing pro-inflammatory cytokines produced by T cells in addition to decreasing IgE levels in a mouse model for rhinitis (nasal passage inflammation). A study using mice with peanut allergies showed that systemic treatment of IL-21 was an effective means of mitigating the allergic response. This has strong implications for the pharmacological development of IL-21 for controlling both localized and systemic allergies.
Role in cancer immunotherapy A role for IL-21 in modulating the differentiation programming of human T cells was first reported by Li et al., where it was shown to enrich for a population of central memory-type CTL with a unique CD28+ CD127hi CD45RO+ phenotype with IL-2 producing capacity. Tumor-reactive antigen-specific CTL generated by priming in the presence of IL-21 led to a stable, 'helper-independent' phenotype. IL-21 is also noted to have anti-tumour effects through continued and increased CD8+ cell response to achieve enduring tumor immunity. IL-21 was approved for Phase 1 clinical trials in metastatic
melanoma (MM) and
renal cell carcinoma (RCC) patients. It was shown to be safe for administration with flu-like symptoms as side effects. Dose-limiting toxicities included low lymphocyte,
neutrophil, and
thrombocyte count as well as hepatotoxicity. According to the Response Evaluation Criteria in Solid Tumors (
RECIST) response scale, 2 out of 47 MM patients and 4 out of 19 RCC patients showed complete and partial responses, respectively. In addition, there was an increase of
perforin,
granzyme B,
IFN-γ, and
CXCR3 mRNA in peripheral
NK cells and CD8+
T cells. This suggested that IL-21 enhances the CD8+ effector functions thus leading to anti-tumor response. IL-21 proceeded to Phase 2 clinical trials where it was administered alone or coupled with drugs as
sorafinib and
rituximab.
Role in viral infections IL-21 may be a critical factor in the control of persistent viral infections. IL-21 (or IL-21R) knock-out mice infected with chronic
LCMV (lymphocytic choriomeningitis virus) were not able to overcome chronic infection compared to normal mice. Besides, these mice with impaired IL-21 signaling had more dramatic exhaustion of LCMV-specific
CD8+ T cells, suggesting that IL-21 produced by
CD4+ T cells is required for sustained CD8+ T cell effector activity and then, for maintaining immunity to resolve persistent viral infection. Thus, IL-21 may contribute to the mechanism by which CD4+ T helper cells orchestrate the immune system response to viral infections. In HIV infected subjects, IL-21 has been reported to critically improve the HIV-specific cytotoxic T cell responses and
NK cell functions. It has also been shown that HIV-specific CD4 T cells from “
HIV controllers” (rare individuals who don’t progress to AIDS by controlling the virus replication without treatment) are able to produce significantly more IL-21 than those of progressors. These data and the fact that IL-21 stimulated CD8 or NK cells are able to inhibit HIV viral replication
in vitro, show that this cytokine could potentially be useful for anti-HIV therapeutics. ==Drug development==