scholarly journals The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Rong Fu ◽  
Shaoxue Ding ◽  
Xiaowei Liang ◽  
Tian Zhang ◽  
Zonghong Shao
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Standard Dose ◽  
Bone Marrow Failure ◽  
Statistical Significance ◽  
Murine Models ◽  
Immune Mediated ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

Recent research has found that Rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved satisfactory effect in clinical application. At present, many studies have confirmed that Eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then whether Rapa combined with Elt in the treatment of AA will be better than single drug application. In this study, we tested efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. Compared with AA group, the whole blood cell count of Rapa+Elt group increased significantly (Figure 1A) (P<0.05). Survival of mice of Rapa+Elt group was significantly higher than that in the Rapa group (p <0.01)(Figure 1B).There was no obvious difference in the numbers of NK cells and their subsets were noted in Rapa group,CsA group and Rapa+Elt group.The expression of NKG2D on peripheral functional NK cells was up-regulated in CsA group, Rapa group and Rapa+Elt group compared with AA group (P<0.05). But there was no significant difference between effect of Rapa and CsA on the function of NK cells (Figure 1C).When Rapa combined with Elt, the expression of CD80 and CD86 are down-regulated more compared to Rapa group, but there is no statistical significance. Although these results suggested that Rapa+Elt had no statistical significance effect on numbers of mDC and expression of its functional molecule CD80 and CD86, the combined therapy still indicated that there is a potential synergy with immunosuppressant on AA mice to improve its outcome (Figure 1D).The results showed that CD4+/CD8+ ratio in CsA group, Rapa group, Rapa + Elt group had an obvious elevation than AA group (all P<0.05). But there were no significant difference among the three groups on the CD4+/CD8+ ratio (Figure 1E,1F). As for INF-gamma, Rapa can reduce the secretion of IFN-γ from CD8+T cells with efficacy similar to that of the standard dose of CsA, and had a better outcome when combined with Elt in bone marrow failure mice (Figure 1E,1G).CsA group, Elt group, Rapa group, Rapa + Elt group showed notable increased ratio of Tregs compared with AA group, among which there were only Rapa group, Rapa + Elt group showed statistical significance(P<0.05). for IL-10/Tregs ratio, Rapa group and Rapa +Elt group were superior to than CsA group(P<0.05) (Figure 1H,1I).Rapa+Elt group and Rapa showed more lower level of IFN-γ compared with CsA group, and there was significant difference in Rapa+Elt group(P<0.05). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO and TNF-α, the Rapa+Elt group showed more significant effect than Rapa or Elt alone(Figure1J). Thus, Rapa+Elt significantly down-regulated cytokines related to Th1 immune responses, such as IFN-γ, and upregulated cytokines related to Th2 immune responses, such as IL-10. To some extent, Rapa combined with Elt has a synergistic effect with CsA and Rapa alone in AA treatment. Conclusions In this study, Although Rapa combined with Elt had no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice compared with Rapa alone, the Rapa+Elt can increase the secretion of IL-10 of Tregs and the number of Tregs, but has no significant effect on the number of Treg cells compared to with Rapa alone. Compared with AA group, the level of plasma IFN-γ, IL-2 and TNF-α decreased significantly (P<0.05), but IL-10, IL-4, IL-5 and IL-1β increased significantly in Rapa group(P<0.05). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO and TNF-α, the Rapa+Elt group showed more significant effect than Rapa alone. intervention treatment with Rapa in combination Elt in the AA mouse model more obviously ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. Combination therapy support potential clinical utility in aplastic anemia treatment, which may further improve the efficacy of AA patients. Keywords: Rapamycin, Eltrombopag, murine models, bone marrow failure Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Shaoxue Ding ◽  
Xiaowei Liang ◽  
Tian Zhang ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Mouse Model ◽  
Mouse Models ◽  
Bone Marrow Failure ◽  
Murine Models ◽  
Curative Effect ◽  
Immune Mediated ◽  
Tnf Α ◽  
Significant Difference

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Most patients with AA respond to immunosuppressive therapy (IST), usually as antithymocyte globulin (ATG) and cyclosporine (CsA), but some relapse on CsA withdrawal or require long-term administration of CsA to maintain blood counts. Recent research has found that rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved a satisfactory effect in clinical application. At present, many studies have confirmed that eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then, whether Rapa combined Elt in the treatment of AA will acquire better efficacy than a single drug application remains unclear. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation (TBI) and allo-lymphocyte infusion. In our study, we tested the efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. It showed that treatment with Rapa in combination Elt in the AA mouse model ameliorated pancytopenia and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. However, there was no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice after the therapy of Rapa combined with Elt compared with Rapa alone. Furthermore, the secretion of IL-10 of Tregs in AA mice increased significantly after the therapy of Rapa combined with Elt, but there was no significant difference in the number of Treg cells. We did not observe the difference in the curative effect of the Rapa group and CsA group, but for IL-10/Tregs ratio, the Rapa group was superior to the CsA group. And the IFN-r secretion of CD8+T cells in AA mice decreased significantly after the combination therapy of Rapa and Elt than Rapa alone. Compared with the AA group, the level of plasma IFN-γ, IL-2, and TNF-α decreased significantly ( P < 0.05 ), but IL-10, IL-4, IL-5, and IL-1β increased significantly in the Rapa group ( P < 0.05 ). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO, and TNF-α, the therapy of Rapa combined with Elt showed a more significant effect than Rapa alone in AA mice. To some extent, this study had shown a relatively better synergistic effect in murine models of immune-mediated bone marrow failure after the combination therapy of Rapa and Elt, which was a promising clinical utility in SAA treatment.

Analysis of Cytokine Profiling in Hepatitis-Associated Aplastic Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1036-1036
Author(s):  
Jun Lu ◽  
Susan Wong ◽  
Atanu Basu ◽  
Neal S. Young ◽  
Kevin E. Brown
Keyword(s):  
Bone Marrow ◽  
Liver Transplantation ◽  
Hepatitis B ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Rnase Protection ◽  
Rna Transcripts ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

Abstract In hepatitis-associated aplastic anemia (HAA), bone marrow failure follows an acute attack of seronegative hepatitis. Aplastic anemia (AA) is also associated with orthotopic liver transplantation for non-A, non-B, non-C hepatitis in young patients. Although the etiology of HAA is unknown, a clinical response to immunosuppressive therapy is observed in most clinical cases. The liver is the potential initial target organ of the immune response. We have previously determined the T-cell repertoire in the liver and peripheral blood lymphocytes in patients with HAA (Lu et al. Blood. 2004 Jun 15;103(12):4588–93). An antigen-driven T-cell expansion was implicated in the acute stage before bone marrow failure. In the present study, we measured serum cytokine levels in 22 HAA serum samples. Only interleukin (IL)-10 levels showed a significant increase compared to healthy controls (p&lt;0.02); IFN-γ , TNF-α and IL-1, 2, 4, 5, 6, 8, 12 levels showed no significant difference. To further characterize the immune response in the liver, we performed RNAse protection assays and realtime PCR for RNA transcripts. In 4 HAA liver samples, 2 demonstrated increased IFN-γ by RNAse protection; TNF-α , IL-2, 3, 4, 5, 10, 15 transcripts were not different compared to transcript levels in 4 hepatitis B and/or C livers and 2 fulminant hepatitis (FH) samples. To confirm our preliminary data, we characterized the cytokine profile including CD4, CD8, CD69, TNF-α , IFN-γ and interleukins and compared them among the hepatitis B/C, FH and HAA liver samples by quantitative PCR for RNA transcripts. In 10 HAA liver samples, CD8 transcripts were increased and the CD4/CD8 ratio was decreased, but there was no significant difference between HAA and hepatitis B/C (p&gt;0.05), confirming the important role of cellular immunity in HAA. IFN-γ transcripts were significantly overexpressed in both HAA and FH samples compared to hepatitis B/C samples (p&lt;0.05), but without a difference between HAA and FH. CD69 transcripts were reduced in HAA but not significantly lower than in hepatitis B/C (p&lt;0.05). There were no difference of TNF-α transcripts among HAA, hepatitis and FH samples (p&gt;0.05). In summary, our data confirm that enhanced cellular immunity (increased IFN-γ level) is implicated in the pathogenesis of HAA, similar to that observed in the bone marrow of idiopathic AA, and in contrast to other liver diseases such as chronic hepatitis B/C. Quantitation of IFN-γ levels in acute hepatitis samples might be a predictive marker for the development of bone marrow failure after liver transplantation following seronegative hepatitis and FH.

scholarly journals Macrophage TNF-α licenses donor T cells in murine bone marrow failure and can be implicated in human aplastic anemia

Blood ◽  
2018 ◽  
Vol 132 (26) ◽  
pp. 2730-2743 ◽  
Author(s):  
Wanling Sun ◽  
Zhijie Wu ◽  
Zenghua Lin ◽  
Maile Hollinger ◽  
Jichun Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Murine Bone Marrow ◽  
Immune Mediated ◽  
Tnf Α ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α−/− donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR−/− recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α−/− recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α−/− recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR−/− donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α–producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.

scholarly journals Rapamycin targets several pathophysiological features of immune-mediated bone marrow failure in murine models

Haematologica ◽  
2017 ◽  
Vol 102 (10) ◽  
pp. 1627-1628 ◽  
Author(s):  
Wendy W. Weston ◽  
Vesna Jurecic ◽  
Roland Jurecic
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Murine Models ◽  
Immune Mediated

Tumor Necrosis Factor-Alpha and Interleukin-6 Promoter Gene Polymorphisms in Acquired Bone Marrow Failure Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3707-3707 ◽  
Author(s):  
Vinod K. Gidvani ◽  
Shakti H. Ramkissoon ◽  
Elaine W. Wong ◽  
Lori Mainwaring ◽  
Elaine M. Sloand ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Cytokine Gene ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Bone Marrow Failure Syndromes ◽  
Immune Mediated ◽  
Tnf Α ◽  
Historical Controls ◽  
Pro Inflammatory Cytokines

Abstract Some acquired aplastic anemia (AA) results from immune mediated destruction of the hematopoetic stem cells. Immunosuppressive therapy is successful in majority of AA patients and substantial laboratory data are consistent with an immune pathophysiology. Substantial research has implicated differences in cytokine gene expression profiles and polymorphisms in the genes controlling cytokine expression in other autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. Interlukin-6 (IL-6) and tumor necrosis alpha (TNF-α) are two potent pro-inflammatory cytokines that have implicated in a variety of immune-mediated conditions. TNF-α results in Fas expression and apoptosis of in progenitor cells and the TNF-alpha −308 allele was significantly associated with SLE in Caucasians. Levels both IL-6 and TNF-α have been reported elevated in AA patients. In the promoter region of the IL-6 gene, at position −174, exists a single nucleotide polymorphism (G/C) in close proximity to a glucocorticoid-responsive element; patients homozygous for the G allele have circulating IL-6 concentrations close to twice as high as those homozygous for the C allele. The TNF-α gene, located in the class III region of the major histocompatibility complex (MHC), has a polymorphism at position −308, TNF2, where the presence of adenine instead of guanine is associated with higher cytokine production. In our study, we characterized the IL-6/−174 and the TNF-α/−308 polymorphisms in patients with acquired bone marrow failure syndromes to assess if the higher production genotypes were more prevalent that in established controls. We identified seventy-three patients (age range 3–84) treated at our institution for AA. Following an established protocol for the identification of single nucleotide polymorphisms, genomic DNA was amplified with primers designed for the promoter regions of the IL-6 and TNF-α genes where intentional mismatches were inserted at 1–3 nucleotide positions to incorporate a restriction site for endonucleases. The amplicons were digested with four restriction endonucleases (BlsI, BsaBI, EcoNI, RsaI) then analyzed by electrophoresis in 3% agarose gels. The resulting fragments allowed for the identification and confirmation of the specific nucleotide polymorphism at the 174 and 308 position of the IL-6 and TNF-α promoter, respectively. The frequency of the high cytokine producing genotypes in the cohort was compared to established controls and the statistical significance determined by the two-tailed Fishers exact test. The GG genotype of the IL-6/−174 polymorphism was present in 32 of 73 (44%) of affected patients versus 80 of 250 (32%) historical controls of the control population (p =0.0698) while the AA genotype of the TNF-α/−308 polymorphism was found in 8 of 73 AA patients (11%) and in only 9 of 354 historical controls (2.5%) (p= 0.0034). Three of 73 AA patients had both gene polymophisms p<0.0001. Two patients’ BM was cultured and ELISA performed for TNF-α as part of a larger study, which included 20 normal controls and 30 patients with marrow failure; both of these patients demonstrated significant elevations in TNF-α. In conclusion, we showed that some patients with acquired bone marrow failure have cytokine gene polymophisms which are linked to high production of pro-inflammatory cytokines, particularly TNF-α.

Bone Marrow Cellular Composition and Inflammatory Cytokine Expression in Patients with Inherited Bone Marrow Failure Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4401-4401
Author(s):  
Neelam Giri ◽  
Ken Matsui ◽  
Blanche P Alter ◽  
Sharon A Savage ◽  
Yuanji Pan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Bone Marrow Failure Syndromes ◽  
Cd34 Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Abstract 4401 Proinflammatory cytokines, TNF-α and IFN-γ, are potent inhibitors of hematopoiesis, and may be relevant in the pathogenesis of bone marrow failure in inherited bone marrow failure syndromes (IBMFS). Increased levels of these cytokines in sera and in bone marrow CD3+ cells have been reported in Fanconi anemia (FA) patients. However, our study did not find increased TNF-α or IFN-γ in sera, or supernatants from phytohemagglutinin-stimulated peripheral blood mononuclear cells from IBMFS patients. To assess whether production of these cytokines is dysregulated in BM of these patients, we examined intracellular expression of TNF-α and IFN-γ in BM mononuclear cells from 16 FA, 20 dyskeratosis congenita (DC), 21 Diamond-Blackfan anemia (DBA) and 7 Shwachman-Diamond syndrome (SDS) patients by flow cytometry; 14 healthy adults were studied as controls. To detect intracellular TNF-α and IFN-γ, BM lymphocytes and monocytes were stimulated with phorbol 12-myristate 13-acetate plus ionomycin (P+I), or lipopolysaccharide (LPS), respectively. Separately, unstimulated cells were stained with antibodies to CD45, CD3, CD19, CD14, and CD34 to determine the proportion of cellular subsets. Percentages of T cells in patients with IBMFS were comparable to the controls, while DC patients had lower proportion of B cells (p=0.02). The percentages of monocytes were lower in FA (p=0.04), DC (p=0.009), and DBA (p<0.001) patients. The proportions of CD34+ cells were also lower in IBMFS patients (≤0.02 for all) except for those with DBA, who had similar proportions as the controls. When we compared the effect of cytopenia (counts below normal for age), only the proportion of CD34+ cells in DC patients was significantly affected. DC patients with cytopenia (n=15) had lower numbers of CD34+ cells (p=0.007) compared with those without (n=5). We also analyzed the effect of somatic mosaicism in FA because it may correct the hematopoietic defect in these patients. FA patients without mosaicism (n=11) had lower proportions of CD19+, CD14+, and CD34+ cells than those with mosaicism (n=5), while the CD3+ cell numbers were unaffected. We detected both intracellular TNF-α and IFN-γ in T cells, but only TNF-α in B cells in response to P+I, while LPS stimulation led to TNF-α production only in monocytes. Percentages of cytokine-producing T and B cells were significantly lower for patients with DBA when compared with healthy adult controls (p<0.006 for T cells and p=0.001 for B cells). There were no significant differences in the other syndromes. Comparison of intracellular cytokines between cytopenic and non-cytopenic patients showed that TNF-α-producing T cells were affected in FA (p=0.03), where the cytopenic patients had a higher proportion of TNF-α-positive T cells. For the LPS-stimulated monocytes, FA (p=0.01) and DBA (p=0.05) patients had significantly lower proportions of TNF-α-producing cells than the controls, and this was independent of cytopenia. There was no effect of mosaicism on cytokine production. Contrary to previous reports, we did not find an increase in intracellular TNF-α or IFN-γ in T cells from FA patients. However, the number of TNF-α-producing monocytes in FA was lower than that in healthy adult controls. This is consistent with reported dysregulation of monocytes in FA patients. We also identified reduced cytokine expression in lymphocytes and monocytes from DBA patients, but not from DC or SDS. As expected, we found reduced proportions of CD34+ cells in FA, DC and SDS, syndromes associated with multilineage cytopenia, and not in DBA which is associated with pure red cell aplasia. And, we ascertained that FA patients with somatic mosaicism had significantly higher percentages of cells including CD34+, suggesting that the corrected stem cell pool in FA mosaics is able to maintain hematopoiesis in contrast to non-mosaic FA patients who develop progressive cytopenia over time. Overall, the effect of cytopenia on cytokine production was mild; however, this may be related to the small sample size. In conclusion, our results suggest that mechanisms other than an excess of inflammatory cytokines may be responsible for bone marrow failure in IBMFS, and this area of research deserves a further attention in larger studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ripk-Mediated Necroptosis Induces Inflammation and Bone Marrow Failure in Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1599-1599
Author(s):  
Justine E. Roderick ◽  
Nicole Hermance ◽  
Matija Zelic ◽  
Matthew Simmons ◽  
Apostolos Polykratis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Type I ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Ifn Γ

Abstract TNF-α and IFN-γ overproduction are features associated with human bone marrow failure syndromes such as Fanconi Anemia (FA) and Aplastic Anemia (AA). Cells from these patients are known to be hypersensitive to TNF-α and IFN-γ-induced cell death. The serine threonine kinases RIPK1 and RIPK3 interact to mediate necroptosis induced by TNF-α, type I or II interferons. We demonstrate that a hematopoietic RIPK1 deficiency results in hematopoietic stem and progenitor cell loss and induction of bone marrow failure. The cell death reflects cell-intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. Hematopoietic failure in these mice is accompanied by increases in serum pro-inflammatory cytokines/chemokines and reduced hematopoietic colony formation in the presence of TNF-α, type I or II interferon. We provide genetic evidence that a RIPK3 deficiency rescues the bone marrow failure and significantly reduces serum cytokine and chemokine levels in Vav-iCre Ripk1fl/fl mice. These data reveal that in the hematopoietic lineage RIPK1 prevents inflammation by suppressing RIPK3 activity and raise the possibility that human bone marrow failure patients may benefit from selective RIPK inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rapamycin is highly effective in murine models of immune-mediated bone marrow failure

Haematologica ◽  
2017 ◽  
Vol 102 (10) ◽  
pp. 1691-1703 ◽  
Author(s):  
Xingmin Feng ◽  
Zenghua Lin ◽  
Wanling Sun ◽  
Maile K. Hollinger ◽  
Marie J. Desierto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Murine Models ◽  
Immune Mediated ◽  
Highly Effective

scholarly journals Increased Levels of CD107a and Intracellular Cytokines in IL-2 Stimulated PBMCs from Endometriosis Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
R. Muharam ◽  
Ririn Rahmala Febri ◽  
Kevin Ardito Prabowo ◽  
Arleni Bustami ◽  
Indra G. Mansur
Keyword(s):  
Nk Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Surface Marker ◽  
Target Cells ◽  
Intracellular Cytokines ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ ◽  
Marker Cd107a

It has been postulated that the immune system is impaired in individuals with endometriosis, with attention directed to natural killer (NK) cells. Specifically, it has been hypothesized that altered numbers of peripheral NK cells in blood are associated with the presence of endometriotic lesions. This study aimed to evaluate the level of the peripheral NK cell surface marker CD107a in endometriosis in the presence of IL-2 stimulation. Peripheral blood mononuclear cells (PBMCs) were obtained from 7 women with endometriosis and 7 women without endometriosis. The PBMCs were divided into two groups and either treated with recombinant IL-2 or left untreated. The cytotoxic activity of the PBMCs toward target cells (K562) was evaluated. Then, both groups were cocultured for 4 days. The expressions of CD107a, TNF-α, and IFN-γ were determined using flow cytometry analysis. There was no difference in the expression of CD107a prior to IL-2 stimulation in PBMCs from women with endometriosis compared to those from women without endometriosis. However, we observed upregulation of the expression of the surface marker CD107a after treatment in the endometriosis group. In addition, there was a significant difference in CD107a expression in the endometriosis group before versus after stimulation with IL-2 ( p  < 0.01). We also found no difference in the production of TNF-α and IFN-γ before versus after treatment with IL-2 in either groups. The levels of CD107a were significantly enhanced in peripheral blood taken from women with endometriosis after treatment with IL-2.

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