Free Radical and Oxidative Damage
in Human Blood Cells

Chiu, Daniel T.; Liu, Tsan Zon

doi:10.1159/000457009

Cited by 17 publications

(19 citation statements)

References 19 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Immunological studies of 9 commonly used therapeutic mAb that are very different in specificity and biochemistry were found to manifest autoantibody activity after incubation with hemin ( Table 1). Hemin is a normal degradation product of hemoglobin, 12 and thus is found at sites where erythrocytes are destroyed. 13 Very little data are available on plasma concentrations of hemin, but it has been reported as 50-280 lM in patients with b-Thalassemia.…”

Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

View full text Add to dashboard Cite

We and others have reported that multiple autoantibodies are unmasked in human polyclonal antibody preparations after exposure to physiological oxidizing agents (hemin) or electromotive force. We now have asked if oxidation unmasks autoantibody reactivities in monoclonal antibodies (mAb). To do this, we have studied 9 FDA approved mAb used therapeutically, including 4 chimeric, 4 humanized and 1 chemically modified chimeric Fab that were exposed to the physiological oxidizing agent hemin at 36°C for 20 hr. These mAb were studied for autoantibody activity to phospholipids and DNA before and after oxidation with hemin and found to develop autoantibody activities after oxidation, while retaining their original specificity as measured by mAb anti-glycophorin A binding of erythrocytes, CD 19 binding to B lymphocytes and anti-HLA-A29 binding to A29-positive lymphocytes. The finding that certain mAb have the potential to unmask autoantibody activities as a consequence of exposure to physiological redox reactions in vitro gives pause to our present understanding of the immunological basis of tolerance and concern for potential autoimmune side effects in patients receiving mAb for diagnosis or treatment.Genetic engineering is a growth strategy in the design and development of monoclonal antibodies (mAb) for clinical therapeutics, such as drug targeting in cancer chemotherapy.1,2 However, the clinical use of mAb has been associated with serious side effects, 3 presumably due to collateral damage from reactions with antigens of unintended targets. 4 Inasmuch as a tenant of the scientific basis for the clinical use of mAb is that they react only with one or a small number of closely related epitopes, 5 we asked if their specificities might be altered by exposure to physiological concentrations of physiological oxidants known to participate in physiological redox reactions. We posed this query due to our earlier reports of the unmasking of autoantibody activities in human blood as well as in purified IgG that had been exposed to such physiological redox reactions. 6 One might then ask why such redox-reactive antibodies exist. We have proposed that redox-reactive antibodies represent elements of the body's immune defense and surveillance network. 7 Recently, a similar explanation has been put forward by others. 8 In the following paragraphs, we present data indicating that autoimmune activities can be unmasked in solutions of FDA approved mAb of several different specificities and immunochemistries. Material and MethodsThe experimental design and techniques used in this study are the same as those used in our earlier report of the unmasking of autoantibody activity in human IgG following oxidation with physiological oxidants such as hemin 6 or by using electromotive force (EMF).9 It was shown that hemin was responsible for oxidation of the antibody because (i) none of the antibody changes occurred in the absence of hemin, (ii) none of the antibody changes occurred in the presence of hemopexin, which is a biological inhibitor ...

show abstract

Section: Resultsmentioning

confidence: 99%

Autoantibody potential of cancer therapeutic monoclonal antibodies

McIntyre

Faulk

2010

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…3). RBCs are well equipped with the powerful antioxidant system and it is difficult to develop oxidative stress within RBC but studies indicate that during RBC aging methemoglobin mediated ROS production causes development of oxidative stress [47]. Oxidative stress in RBC causes membrane protein modification resulting in development of charge on the outer membrane.…”

Section: Discussionmentioning

confidence: 99%

Extracellular methemoglobin primes red blood cell aggregation in malaria: An in vitro mechanistic study

Balaji

Trivedi

2013

FEBS Letters

View full text Add to dashboard Cite

Toxic byproducts from infected RBC cause rheological alteration and RBC aggregation. Malaria culture supernatant has the ability to exhibit RBC aggregation. Ammonium sulfate fractionation and immunodepletion of methemoglobin from culture supernatant confirms methemoglobin as a major aggregant. In vitro treatment of RBC with methemoglobin induces irreversible high order RBC aggregates, resistant to shear stress and physical forces. Methemoglobin-mediated ROS generation in the external micro-environment to develop oxidative stress close to RBC membrane seems to be responsible for initiating and forming high order RBC aggregates through phosphatidyl-serine externalization. Removal of oxidative stress through antioxidant treatment abolishes high order RBC aggregate formation. In conclusion, we discovered a novel pathway of methemoglobin-mediated RBC aggregation and its potential role in patho-physiological effects during malaria.

show abstract

“…Hemin was studied because its coordinated iron mediates redox control of masking/unmasking reactions, and because of its biological availability in vivo. For example, hemoglobin denatures to hemin in aging erythrocytes [9], and phosphatidylserine (PS) translocates to plasma membranes [10], positioning hemin to unmask autoantibodies to PS, which could opsonize the aging cells for immunological removal. Similarly, human extra embryonic membranes as well as tumor cells express both PS [11,12] and transferrin receptors on their surfaces [13e15], positioning the up-regulated PS and receptor-bound transferrin-iron to provide changes in redox potential that unmask blocking antibodies, as previously proposed [15,16].…”

Section: Discussionmentioning

confidence: 99%