Intracellular iron overload leading to <scp>DNA</scp> damage of lymphocytes and immune dysfunction in thalassemia major patients

Shaw, Jyoti; Chakraborty, Ayan; Nag, Arijit; Chattopadyay, Arnab; Dasgupta, Anjan Kr.; Bhattacharyya, Maitree

doi:10.1111/ejh.12936

Cited by 31 publications

(22 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Iron can trigger CD4 + differentiation towards a T H 2 phenotype (14,29) and impact on CD8 + cell numbers (30). A similar impairment of T cell function has been observed in individuals with hereditary or transfusion mediated iron overload (31,32).…”

Section: Introductionmentioning

confidence: 75%

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

et al. 2020

View full text Add to dashboard Cite

Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, tumor proliferation, anti-tumor T cell responses and, of clinical importance, on efficacy of cancer immunotherapies. Herein, we analyzed the effects of intravenous iron supplementation on T cell function and on the effectiveness of anti-cancer chemotherapy with IL-2/doxorubicin or immunotherapy with checkpoint-inhibitor anti-PD-L1 in C57Bl/6N female mice with implanted E0771 mammary carcinomas. We found that iron application resulted to an increased availability of iron in the tumor microenvironment and stimulation of tumor growth. In parallel, iron application inhibited the activation, expansion and survival of cytotoxic CD8+ T cells and of CD4+ T helper cells type 1 and significantly reduced the efficacy of the investigated anti-cancer treatments. Our results indicate that iron administration has a tumor growth promoting effect and impairs anti-cancer responses of tumor infiltrating T lymphocytes along with a reduced efficacy of anti-cancer therapies. Iron supplementation in cancer patients, especially in those treated with immunotherapies in a curative setting, may be thus used cautiously and prospective studies have to clarify the impact of such intervention on the outcome of patients.

show abstract

Section: Introductionmentioning

confidence: 75%

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The latter, in turn, may lead to oxidative stress aggravating brain tissue damage [60]. Moreover, accumulation of intracellular iron may cause DNA fragmentation, which may ultimately damage lymphocyte functions, leading to immune dysfunction and increased susceptibility to infections in β-TM patients [61].…”

Section: Discussionmentioning

confidence: 99%

Major Depression in Children with β-Thalassemia Major is Strongly Associated with the Number of Blood Transfusions, Iron Overload and Increased Levels of Interleukin-1β

Al‐Hakeim¹,

Najm²,

Al-Aldujaili³

et al. 2019

Preprint

View full text Add to dashboard Cite

Beta-thalassemia major (β-TM) patients are treated with repeated blood transfusions, which may cause iron overload (IO), which in turn may induce immune aberrations. Patients with β-TM have an increased risk of major depressive disorder (MDD). The aims of the present study are to examine whether repeated blood transfusions, IO and immune-inflammatory responses are associated with MDD in children (6-12 years) with β-TM. The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%) and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in β-TM with (n=54) and without (n=57) MDD and in healthy children (n=55). The results show that MDD in β-TM is associated with a greater number of blood transfusions, increased IO and IL-1β levels. Partial Least Squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, IO, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of IO on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by IO and the path from IO to immune activation. IO is also associated with increased IL-10 and lower CCL11 levels but these alterations are not significantly associated with MDD. In conclusion, blood transfusions may be causally related to MDD in β-TM children and their effects are in part mediated by increased IO and the consequent immune-inflammatory response. The results suggest that not only IO and its consequences including inflammation and ferroptosis, but also other factors related to the number of transfusions may cause MDD including psychosocial stressors. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate IO and immune-inflammatory responses and to prevent MDD is children with β-TM undergoing blood transfusions.

show abstract

“…Samples were collected after obtaining written informed consent from the subjects. The selection and evaluation of study subjects are detailed in our recent publication[13]. In the present study, blood sample were collected from the subjects in EDTA and heparin vacutainer, for RBC and lymphocyte isolation, respectively with informed consents as prescribes by the ethical committee.…”

Section: Methodsmentioning

confidence: 99%

“…Firstly lymphocytes were isolated and treated from both thalassemia patients and controls following the protocol described by Shaw et al [13]. Lymphocytes suspension were first divided into two sets of tubes.…”

Section: Methodsmentioning

confidence: 99%

Chelation Therapy Using Static Magnetic Field

Shaw¹,

Chakraborty²,

Chatterjee

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Static magnetic field (SMF) is reported to mimic chelation agents. In thalassemia blood, SMF minimizes iron overloading effect. In such cells ROS level is reduced, in presence of moderate strength (70mT). Pilot study on transfusion dependent thalassemia, thalassemia carriers and normal red blood clearly indicate the differential effects of SMF on thalassemia, thalassemia carrier and normal cells. SMF also reduces ROS induced DNA damage in lymphocytes. A comparative study on the iron chelating drug deferasirox and SMF treated lymphocytes further confirm our main thesis. This non-invasive therapeutic regime for hemochromatosis may serve the dual purpose of treating, iron overloading and minimizing, cellular damage by lowering the ROS level.

show abstract

Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients

Cited by 31 publications

References 40 publications

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Major Depression in Children with β-Thalassemia Major is Strongly Associated with the Number of Blood Transfusions, Iron Overload and Increased Levels of Interleukin-1β

Chelation Therapy Using Static Magnetic Field

Contact Info

Product

Resources

About

Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients

Cited by 31 publications

References 40 publications

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Major Depression in Children with &beta;-Thalassemia Major is Strongly Associated with the Number of Blood Transfusions, Iron Overload and Increased Levels of Interleukin-1&beta;

Chelation Therapy Using Static Magnetic Field

Contact Info

Product

Resources

About

Major Depression in Children with β-Thalassemia Major is Strongly Associated with the Number of Blood Transfusions, Iron Overload and Increased Levels of Interleukin-1β