Effects of Irradiation on the &lt;i&gt;in vitro &lt;/i&gt;Immune Response

Anderson, Robert E.; Lefkovits, Ivan

doi:10.1159/000162993

Cited by 20 publications

(25 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent report gives data that were interpreted to show carrier-mediated transport across the blood-brain barrier in the rat; uptake was reported as saturable with an apparent Km value of 5.84 mM (52). The data presented do not provide a value for uptake at physiological levels of plasma GSH (-22-27 ,uM) (53). Although acivicin (an inhibitor of -y-glutamyl transpeptidase) was administered (52), y-glutamyl transpeptidase would not be predicted to be completely inhibited under these conditions (54).…”

Section: Resultsmentioning

confidence: 75%

Glutathione deficiency leads to mitochondrial damage in brain.

Jain

Mårtensson²,

Stole³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

386

186

View full text Add to dashboard Cite

Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of y-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration ofthe mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t ., -30 min in adults, ==8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by y-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn.Studies in which glutathione (GSH) deficiency was induced in animals by administering L-buthionine (S,R)-sulfoximine (BSO) (1, 2), a transition-state inhibitor of y-glutamylcysteine synthetase (3,4), showed that GSH deficiency leads to myofiber degeneration in skeletal muscle (5), damage to type 2-cell lamellar bodies and capillary endothelial cells in the lung (6), and epithelial-cell damage to jejunum and colon (7) in adult mice, and to lens epithelial-cell degeneration and cataract formation in newborn mice (8, 9) and rats (9). These effects, which were invariably accompanied by markedly decreased mitochondrial GSH levels, were associated with mitochondrial swelling with vacuolization and rupture of cristae and mitochondrial membranes as seen by EM. The isolated mitochondria exhibited decreased citrate synthase activity.It should be emphasized that these effects occurred without application of stress (e.g., increased oxygen, drugs, radiation) and that they were completely prevented by administration of GSH monoesters (10-13). In the absence of evidence that BSO itself exerts a separate type of toxicity other than its effect on the enzyme that catalyzes the first step of GSH synthesis, it may be concluded that a major effect of GSH deficiency is mitochondrial damage. Although mitochondria have long been known to contain GSH, only recently was mitochondrial GSH found to originate from the cytosol and to be imported into mitochondria by a system that contains a high-affinity transporter (14,15). Not all oxygen used by mitochondria is reduced to water, but a significant fraction of it is converted, apparently throu...

show abstract

Section: Resultsmentioning

confidence: 75%

Glutathione deficiency leads to mitochondrial damage in brain.

Jain

Mårtensson²,

Stole³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

386

186

View full text Add to dashboard Cite

show abstract

“…Previous studies have demonstrated that memory B cells are easily depleted by irradiation, [45][46][47] but plasma cells are notably radiation resistant. 47,48 Recently, studies have shown that plasma cells can survive for more than 90 days in bone marrow and spleen in lymphocytic choriomeningitis virus-immune mice that were given 600 cGy of TBI.…”

Section: Discussionmentioning

confidence: 99%

“…Our results demonstrated that long-term engraftment of 2bf8 genetically modified HSCs was achieved in immunized recipients conditioned with either lethal (1100 cGy) or sublethal irradiation (Ն 440 cGy). Long-term 2bF8 engraftment was assessed by real-time PCR and platelet lysate FVIII:C assays for a follow-up period of 8 months after BMT.Previous studies have demonstrated that memory B cells are easily depleted by irradiation, [45][46][47] but plasma cells are notably radiation resistant. 47,48 Recently, studies have shown that plasma cells can survive for more than 90 days in bone marrow and spleen in lymphocytic choriomeningitis virus-immune mice that were given 600 cGy of TBI.…”

mentioning

confidence: 99%

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

Shi

Fahs

Wilcox

et al. 2008

Blood

123

View full text Add to dashboard Cite

Although genetic induction of factor VIII (FVIII) expression in platelets can restore hemostasis in hemophilia A mice, this approach has not been studied in the clinical setting of preexisting FVIII inhibitory antibodies to determine whether such antibodies would affect therapeutic engraftment. We generated a line of transgenic mice (2bF8) that express FVIII only in platelets using the platelet-specific ␣IIb promoter and bred this 2bF8 transgene into a FVIII null background. Bone marrow (BM) from heterozygous 2bF8 transgenic (2bF8 tg؉/؊ ) mice was transplanted into immunized FVIII null mice after lethal or sublethal irradiation. After BM reconstitution, 85% of recipients survived tail clipping when the 1100-cGy (myeloablative) regimen was used, 85.7% of recipients survived when 660-cGy (nonmyeloablative) regimens were used, and 60% of recipients survived when the recipients were conditioned with 440 cGy. Our further studies showed that transplantation with 1% to 5% 2bF8 tg؉/؊ BM cells still improved hemostasis in hemophilia A mice with inhibitors. These results demonstrate that the presence of FVIII-specific immunity in recipients does not negate engraftment of 2bF8 genetically modified hematopoietic stem cells, and transplantation of these hematopoietic stem cells can efficiently restore hemostasis to hemophilic mice with preexisting inhibitory antibodies under either myeloablative or nonmyeloablative regimens. IntroductionHemophilia A is a severe congenital bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). 1 Currently, hemophilia is treated with protein replacement therapy using either plasmaderived or recombinant FVIII. 2 Although FVIII replacement markedly improves the life expectancy of patients with hemophilia, up to 30% of patients with severe hemophilia A develop antibodies after FVIII replacement therapy. [3][4][5][6][7] These antibodies cause the clinical failure of treatment in response to routine replacement therapy for bleeding episodes and therefore are referred to as FVIII inhibitors. [8][9][10] Clinically, inhibitor titers greater than 5 Bethesda units (BU)/mL are considered untreatable using routine FVIII replacement. 11 Induction of immune tolerance to the FVIII protein is a treatment option for the eradication of anti-FVIII inhibitors, but it is very expensive and may not always be effective. [12][13][14] Infusion of NovoSeven (FVIIa) may also restore hemostasis in patients with inhibitors, but it is more costly because of its short half life and may result in thrombotic complications. [15][16][17] Gene therapy could be an alternative treatment for hemophilia A. There has been substantial progress in gene therapy of hemophilia A in preclinical trials. [18][19][20][21][22][23][24][25][26][27][28][29] Gene therapy of hemophilia A with preexisting FVIII immunity is especially challenging because circulating inhibitory antibodies in plasma may inactivate functional FVIII if it is constitutively secreted into plasma. Therefore, developing a mechanism for secure cellular del...

show abstract

“…There is evidence that intracellular compartmentalization of GSH occurs (34 -36). GSH levels in blood plasma are quite low (25 M) (37). The regeneration of GSH is mainly controlled by glutathione disulfide reductase (30).…”

Section: Discussionmentioning

confidence: 99%

The Fate of the Oxidizing Tyrosyl Radical in the Presence of Glutathione and Ascorbate

Sturgeon

Sipe

Barr

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cellular systems contain as much as millimolar concentrations of both ascorbate and GSH, although the GSH concentration is often 10-fold that of ascorbate. It has been proposed that GSH and superoxide dismutase (SOD) act in a concerted effort to eliminate biologically generated radicals. The tyrosyl radical (Tyr ⅐ ) generated by horseradish peroxidase in the presence of hydrogen peroxide can react with GSH to form the glutathione thiyl radical (GS ⅐ ). GS ⅐ can react with the glutathione anion (GS ؊ ) to form the disulfide radical anion (GSSG . ). This highly reactive disulfide radical anion will reduce molecular oxygen, forming superoxide and glutathione disulfide (GSSG). In a concerted effort, SOD will catalyze the dismutation of superoxide, resulting in the elimination of the radical. The physiological relevance of this GSH/SOD concerted effort is questionable. In a tyrosyl radical-generating system containing ascorbate (100 M) and GSH (8 mM), the ascorbate nearly eliminated oxygen consumption and diminished GS ⅐ formation. In the presence of ascorbate, the tyrosyl radical will oxidize ascorbate to form the ascorbate radical. When measuring the ascorbate radical directly using fast-flow electron spin resonance, only minor changes in the ascorbate radical electron spin resonance signal intensity occurred in the presence of GSH. These results indicate that in the presence of physiological concentrations of ascorbate and GSH, GSH is not involved in the detoxification pathway of oxidizing free radicals formed by peroxidases.

show abstract

Effects of Irradiation on the <i>in vitro </i>Immune Response

Cited by 20 publications

References 16 publications

Glutathione deficiency leads to mitochondrial damage in brain.

Glutathione deficiency leads to mitochondrial damage in brain.

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

The Fate of the Oxidizing Tyrosyl Radical in the Presence of Glutathione and Ascorbate

Contact Info

Product

Resources

About