For thousands of years till nowadays, Nigella sativa (NS) has served as a common spice and food preservative. Its seed extracts, seed oil, and essential oil in traditional medicine have been used to remedy many ailments such as headaches, fever, gastric complaints, and even rheumatism. In addition, the antibacterial, virucidal, fungicidal, and antiparasitic properties of NS are well known. However, studies on the possible immunomodulatory effects of black cumin are relatively scarce.
1. Studies In Vitro
Haq and colleagues 
examined the effect of phosphate buffer saline (PBS) extract from NS seeds in 50, 5, and 0.5 µg/mL concentrations on human lymphocytes and polymorphonuclear (PMNs) leukocytes. Peripheral blood mononuclear cells (PBMCs) were stimulated with concanavalin A (ConA), phytohemagglutinin (PHA), or pokeweed mitogen (PWM) in the presence of several concentrations of NS extract. The high concentrations of NS extract suppressed the lymphocyte response to all mitogens due to increased cell death. Furthermore, at the highest concentration, NS extract also suppressed the phagocytic activity of PMNs. At the same time, the extract stimulated lymphocytes to secrete interleukin 1beta (IL-1β) and IL-3 but not IL-2. Majdalawieh and colleagues 
examined how NS influences splenocyte proliferation, macrophage function, and natural killer (NK) cell activity in C57/BL6 and BLAB/c cells. The authors demonstrated that the aqueous extract from NS seeds in four doses (1, 10, 50, and 100 g/mL) increased splenocyte proliferation and the secretion of Th2 cytokines responsible for humoral immune responses in a dose-dependent manner by splenocytes. At the same time, it suppressed the secretion of key proinflammatory mediators, that is, tumor necrosis factor-alpha (TNF-α), IL-6, and nitric oxide (NO) by macrophages. Finally, the authors showed that the extract significantly augmented NK cell cytotoxicity against YAC-1 tumor cells. Their study showed that the effect of the NS extract depends on the type of immune cells, as some immune subpopulations were stimulated in the NS presence to proliferate and produce cytokines, while others were inhibited.
Hexane and methanol extracts from NS seeds in a concentration of 10 mg/mL were found to prevent the formation of protein carbonyl and depletion of glutathione (GSH) in L929 fibroblasts exposed to toluene, which confirms that NS has antioxidant potential 
. In 2013, Elmowalid and colleagues 
examined the immunomodulatory effect of an aqueous extract concentration of 10 mg/mL from NS seeds on sheep macrophage functions in vitro. The authors showed that the addition of NS extract caused an increase in phagocytic activity and the capacity to produce NO. In the study by Gholamnezhad et al. 
, ethanolic extract from NS seeds in concentrations of 100, 500, and 1000 µg/mL was examined to see whether it affected rat splenocytes, especially their viability, proliferation, and cytokine secretion. NS extract inhibited the proliferation and decreased the viability of splenocytes stimulated with PHA or ConA in a dose-dependent manner. Higher concentrations of the extract also reduced the secretion of IL-4 and interferon-gamma (IFN-γ) and increased the IFN-γ/IL-4 ratio. In a recent study, Singh et al. 
investigated the immunomodulatory effect of methanolic extract from NS seed in two doses, 125 and 250 μg/mL, on chicken PBMCs. The authors demonstrated that the extract stimulated the expression of inflammatory genes coding IL-1β, IL-4, IL-10, IL-12, IL-13, IFN-β, and IFN-γ.
However, scarce studies on human material have been reported. For example, Koshak and colleagues 
compared the effects of ethanol, aqueous, and supercritical fluid (SCF) extracts from NS seeds in concentrations of 10 and 100 μg/mL on asthma-related mediators of inflammation in human T cells and monocytes. SCF had the most robust suppressive properties; the extracts reduced the release of IL-2, IL-6, and prostaglandin E2 (PGE2) from T cells and monocytes. Alshatwi 
showed that methanolic extract in concentrations of 2.5 and 5.0 μg/mL from NS seeds inhibited the proliferation of T cells stimulated with PHA for 48 h in a dose-dependent manner. However, without PHA stimulation, NS extract stimulated T cells. The NS extract also decreased the expression of genes coding TNF-α, IL-6, and IL-8 in human PBMCs stimulated with PHA. Conversely, in the absence of PHA stimulation, gene expression was increased in the presence of NS extract.
2. Studies In Vivo
The in vivo immunomodulatory properties of extracts from NS seed were also examined in different animal models. For example, intraperitoneal administration of NS methanolic extract increased the total amount of white blood cells (WBC) in BALB/c mice 
. In addition, hexane and methanol extracts prevented the loss of hepatic GSH in male Wistar rats exposed to toluene 
Boskabady and colleagues 
studied the immunomodulatory properties of ethanolic extract from NS seeds in guinea pigs sensitized to ovalbumin (OVA) as an animal model of asthma. The authors showed that NS extract significantly decreased pathological changes in the lungs of animals. The infiltration of eosinophils and lymphocytes, as well as local epithelial necrosis, was reduced. Simultaneously, serum IL-4 and IFN-γ were increased in animals treated with NS extract compared to control animals. These results confirmed the preventive effect of NS extract on lung inflammation. In the latest study by Hikmah and colleagues 
, the influence of ethanol NS extract on renal tissue damage in the pristane-lupus (PIL) mice model has been investigated. The results showed that the percentage of Th17 cells responsible for inflammatory responses, regulatory T cells (Tregs), and macrophages producing IL-6 and IL-23 in lupus mice treated with NS extract was lower compared to PIL mice treated with placebo or steroids. Additionally, the serum anti-dsDNA antibodies were lower in these mice. Additionally, the renal injury was smaller in lupus mice treated with NS extract. These results showed that the ethanolic extract from NS seeds has immunomodulatory properties and prevents kidney injury in lupus mice.
In another study, the immunomodulatory properties of ethanol extract from NS seeds were assessed in dexamethasone-induced immune-suppressed male rabbits 
. Animals were treated for six weeks orally with water, NS extract, and dexamethasone (Dex) in different combinations. The authors reported a significant decrease in the phagocytic activity of the cells in rabbits treated with Dex alone. However, the administration of NS extract simultaneously with Dex or after three weeks of treatment with Dex improved the phagocytic activity. The authors also showed that NS extract improved bone marrow mitotic activity after treatment with Dex.
The properties of NS were also studied in fish 
. In 2012 Elkamel and Mosaad published work that investigated the modulation of the immune system of Nile tilapia
by NS seeds added as a food additive by comparing its properties with fish basic or a CloSTAT diet (diet with the addition of Bacillus subtilis PB6). The authors investigated immune parameters, including serum globulins, WBC counts, and phagocytic activities. Results showed that adding NS seeds significantly increased the serum globulins, WBC count, and phagocytic activity and reduced fish mortality compared with the standard or CloSTAT diet. These effects were even significantly higher when fish were treated with NS seeds combined with the CloSTAT diet.
In another study, the prophylactic properties of water extract from NS seeds were studied in a group of asthmatic patients 
. The study group received boiled NS seed extract for 3 months. Asthma severity and frequency of symptoms per week, and wheezing were analyzed three times: in the beginning, 45 days after treatment, and at the end of the study. All asthma symptoms, frequency of attacks, chest wheezing, and pulmonary function test (PFT) values significantly improved in the second and third visits compared with the beginning of the experiment.