Abstract
The acute-phase protein α1-antirypsin (AAT) has recently been suggested to exert beneficial effects in various immune-associated pathologies, such as graftversus-host disease, rheumatoid arthritis, multiple sclerosis and allogeneic transplantation. These effects have been demonstrated to take place through direct immunomodulation of dendritic cells, macrophages, neutrophils and B cells, while allowing, in a yet inexplicable distinction, intact isolated functions of T cells and NK cells. With such a unique discriminatory targeting of immunocytes, AAT drives immune responses simultaneously towards regulation of inflammation and expansion of antigen-specific regulatory T cells (Tregs). Based on this intriguing activity profile, a concern was raised regarding the impact of chronic treatment with human AAT with respect to susceptibility to tumors and to metastatic spread. Tumor development is linked to inflammatory responses in a manner which largely promotes immune evasion. Local innate immunocytes, such as tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs) and the recently appreciated tumor-associated neutrophils (TANs), are considered instrumental in primary tumor survival. This is accomplished in part by the release of growth factors and cytokines, including VEGF, TGFβ, IL-10 and IL-1 receptor antagonist (IL-1Ra), all of which have been demonstrated to be elevated in inflammatory conditions during AAT therapy. While clinical studies report heightened serum AAT levels in patients with a variety of advanced tumors, there is no evidence to point to a particular pro-tumor effect of AAT, and the possibility that its elevation in the blood might represent a meresystemic marker– rather than an accessory to tumor development– is grossly overlooked. Indeed, preclinical studies reveal significant inhibition of tumor development during treatment with AAT, and prolonged follow-up studies of individuals who receive life-long excessive doses of intravenous AAT do not depict a rise in tumor occurrence. Considering the prospect of AAT being indicated for medical indications to individuals with normal levels of the protein, its relation to tumor immunology is of immense importance. We hereby review the current knowledge regarding some possible roles that AAT may play, both locally and systemically, in the delicate and detrimental arena of tumor immunology.
Highlights
Alpha1-antitrypsin (AAT) is a 52 kDa anti-inflammatory glycoprotein that has recently come to focus as an immune modulator [1,2]
In order for a successful metastatic migration of tumor cells from the primary tumor to the vasculature, tumor-surrounding ECM must be degraded by proteases [93], including MMPs [94,95,96,97] cathepsins [98] and elastase [99,100,101], which are mainly provided by tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) [1]
Being anti-inflammatory, AAT is seemingly in favor of immune evasion, as expanding Tregs and suppressing macrophage responses would appear to impose; when one gathers data from multiple studies and adds-up the particular paths that they address experimentally, one can observe an overall suppression of tumor growth in the presence of AAT
Summary
Alpha1-antitrypsin (AAT) is a 52 kDa anti-inflammatory glycoprotein that has recently come to focus as an immune modulator [1,2]. Guttman O (2015) Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology established that AAT exerts anti-inflammatory activities, and antigen-specific immunoregulatory activities, as evident upon examining the collective outcomes of AAT treatment in several major in vivo models and immune cell types. Much like in the case of M1 and M2 macrophages, mDCs and smDCs are two opposite extremities and a continuum of possible activation states, rather than a binary programming pattern, is predicted to best reflect the state of DC maturation; numerous “intermediate” activation states have been described In this regard, AAT has been shown to significantly favor the occurrence of smDCs [18] in allogeneic transplantation models, and to induce Treg maturation and transplant-specific tolerance. A detailed examination of TADC profiles and functions in AAT-treated animals is strongly required
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
