Reproductive Immunology: Open Access

Editorial

Exosomes are nano-sized vesicles actively produced and released by all cell types of the body including stem cells. They act as intracellular communicators carrying proteins, mRNA, miRNA and DNA as well as expressing cell surface markers inherent to their parent cell. Exosomes are increasing emerging as effective therapeutics in immune and regenerative therapy and as such are becoming an effective alternative to stem cell therapy and an adjunct to immunotherapy.

In pregnancy the maternal adaptive immune responses are suppressed throughout gestation [1] with a bias away from Th1/ Th17 towards Th2 immunity [2] and a migration of maternal Treg cells to the decidua [3]. In the peripheral circulation the mechanisms that regulate this adaptation are not fully understood. Dr McCracken and colleagues have shown that NF-kappaB in central to the regulation of Th1 immunity [4] and have shown that suppression of NF-κB controls the production of Th1 cytokines thus biasing Th2 cytokine production.

Dr McCracken has shown that the signal that facilitates the suppression of Th1 immunity is derived from pregnancy specific exosomes present in maternal plasma [5]. Placental exosomes possess immune suppressive properties via enhancing lymphocyte apoptosis and suppressing CD3ζ expression, a signalling moiety required for T-cell receptor activation [5,6]. Exosomes derived specifically from placental cultures express ULBP1-5 and Major histopatibility complex 1 and 2 on their surface and induced down-regulation of the NKG2D receptor on NK, CD8(+) cells and gamma delta T cells, leading to reduction of their in vitro cytotoxicity [7] which in vivo would ultimately lead to fetal sparing.

In pregnancy a failure of immune adaptation is associated with complications including recurrent pregnancy loss pre-eclampsia, preterm delivery [8,9] and intra uterine growth restriction (IUGR) [10]. In addition, inducing Treg function using anti-CD28, rescues the IUGR, but not the pre-clamptic symptom in a rat model of preeclampsia and IUGR [11]. This only highlights the importance of maternal immune adaptation in successful fetal growth.

So could we use exosomes derived from the placenta to correct the immunological deficits associated with some or all of these pregnancy complications? Are all exosomes equal in their function?

Exosome function is dictated by their parent cell type. Not unlike exosomes derived from the placenta, tumour derived (TD) exosomes play a critical role in tumour metastasis by suppressing the function of NK and T-cell through the induction of apoptosis [12,13], thus allowing immune evasion and subsequent tumour growth. In addition however although tumour derived exosomes are predominantly known for their immunosuppressive qualities, they can also enhance immune-stimulation, mainly through antigen presentation of tumour antigens by APCs which in its self incites T-cell responses. This can and has been utilised in clinical trials to assess efficacy in treating cancer with increasing promise [14,15]. In addition, although MSCs are extensively used in regenerative and immunotherapy it is become increasingly more evident that the function of many MSCs used in therapy is not due to MSC interactions with affected tissue and cell types, more it is the release and effect of MSC specific exosomes. A realisation Dr Rebecca Lim from the Hudson Institute of Medical Research Australia is investigating with regards to the use of fetally derived amniotic epithelial stem cell exosomes in lung repair both in the adult and the neonate.

Overall the use of exosomes as therapeutic modalities is highly feasible. Their production is cheap and they can be isolated easily by differential ultracentrifugation. In addition they can be purified, frozen, lyophilized, packaged and distributed like any other current drug products, indeed not unlike current FDA-approved liposome therapies. Dr McCracken’s group is working towards fully defining the role of placentally derived exosomes in modulating the immune system in pregnancy and determining their potential use in correcting pregnancy complications. If exosomes can be used to correct these maternal complications this will have considerable impact in both short and long term health outcomes and will be of immense benefit for both mothers and their babies.

References

1. Kieffer TE, Faas MM, Scherjon SA, Prins JR (2016) Pregnancy persistently affects memory T cell populations. J Reprod Immunol 119: 1-8.
2. McCracken SA, Gallery E, Morris JM (2004) Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success. J Immunol 172: 4583-4591.
3. Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM, Kleijburg C, et al. (2008) Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol 180: 5737-5745.
4. Hadfield KA, McCracken SA, Ashton AW, Nguyen TG, Morris JM (2011) Regulated suppression of NF-kappaB throughout pregnancy maintains a favourable cytokine environment necessary for pregnancy success. J Reprod Immunol 89: 1-9
5. McCracken S, Hadfield K, Yenson M, Ariyakumar G, McKelvey K, et al. (2016) NF-kappaB regulation in T-cells in pregnancy is mediated via Fas/FasL interactions: the signal for which is derived from exosomes present in maternal plasma The Signal for which is Derived from Exosomes Present in Maternal Plasma. Reproductive Immunol ogy: Open Access 2016.
6. Taylor DD, Bohler HC, Gercel-Taylor C (2006) Pregnancy-linked suppression of TcRsignaling pathways by a circulating factor absent in recurrent spontaneous pregnancy loss (RPL). Mol Immunol 43: 1872-1880.
7. Hedlund M, Stenqvist AC, Nagaeva O, Kjellberg L, Wulff M, et al. (2009) Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol 183: 340-351.
8. Raghupathy R, Makhseed M, Azizieh F, Omu A, Gupta M (2000) Cytokine production by maternal lymphocytes during normal human pregnancy and in unexplained recurrent spontaneous abortion. Hum Reprod 15: 713-718.
9. Piccinni MP (2006) T cells in normal pregnancy and recurrent pregnancy loss. Reprod Biomed Online 13: 840-844.
10. Prins JR, Faas MM, Melgert BN, Huitema S, Timmer A, et al. (2012) Altered expression of immune-associated genes in first-trimester human decidua of pregnancies later complicated with hypertension or foetal growth restriction. Placenta 33: 453-455.
11. Przybyl L, Ibrahim T, Haase N, Golic M, Rugor J, et al. (2015) Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia. Hypertension 65: 1298-1306.
12. Liu C, Yu S, Zinn K, Wang J, Zhang L, et al. (2006) Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 176: 1375-1385.
13. Taylor DD, Gercel-Taylor C, Lyons KS, Stanson J, Whiteside TL (2003) T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clin Cancer Res 9: 5113-5119.
14. Morse MA, Garst J, Osada T, Khan S, Hobeika A, et al. (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3: 9.
15. Escudier B, Dorval T, Chaput N, Andre F, Caby MP, et al. (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 3: 10.