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January 1987, Vol 122, No. 1 >
ARTICLE | January 1987

Inhibition of Early Events in the Human T-Lymphocyte Response to Mitogens and Alloantigens by Hydrogen Peroxide FREE

Brian M. Freed, MA; Robert Rapoport; Neil Lempert, MD
[+] Author Affiliations

Accepted for publication Aug 11, 1986.

Read before the Sixth Annual Meeting of the Surgical Infection Society, Chicago, April 22, 1986.

Reprint requests to Transplantation Immunology Laboratory, Department of Surgery, Albany Medical College of Union University, Albany, NY 12208 (Dr Lempert).


Arch Surg. 1987;122(1):99-104. doi:10.1001/archsurg.1987.01400130105016
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• Hydrogen peroxide (100 to 200μM) inhibited the response of human peripheral-blood mononuclear cells (PBMCs) in phytohemagglutinin, concanavalin A, and mixed lymphocyte culture assays by more than 90% without affecting cell viability. The response of PBMCs to pokeweed mitogen was stimulated twofold by 50μM H2O2, but 200μM H2O2 inhibited the pokeweed mitogen response by more than 95%. A 50μM concentration of H2O2 completely blocked the generation of cytotoxic T cells in the mixed lymphocyte culture but did not inhibit the production of interleukin 2. Concentrations of 100μM to 200μM H2O2 inhibited interleukin 2 production by 45% to 57%. The H2O2 appeared to block early events in T-cell activation, since 200μM H2O2 was not inhibitory when added one hour after stimulating the cells with phytohemagglutinin. Treatment of PBMCs with 200μM H2O2 did not decrease the total cellular thiol pool, suggesting that H2O2-mediated inhibition of the proliferative response was not due to thiol oxidation. However, pretreatment of PBMCs with the lipid antioxidants butylated hydroxyanisole, butylated hydroxytoluene, and n-propyl gallate blocked more than 75% of the inhibitory effect of H2O2, suggesting that H2O2 inhibits T-cell activation by inducing lipid peroxidation.

(Arch Surg 1987;122:99-104)

REFERENCES

1 +
Miller CL, Baker CC:  Changes in lymphocyte activity after thermal injury: The role of suppressor cells . J Clin Invest 1979;;63:202-210.
2 +
Munster AM, Winchurch RA, Birmingham WJ, et al:  Longitudinal assay of lymphocyte responsiveness in patients with major burns . Ann Surg 1980;;192:772-775.
3 +
Mclrvine AJ, O'Mahony JB, Saporoschetz I, et al:  Depressed immune response in burned patients: Use of monoclonal antibodies and functional assays to define the role of suppressor cells . Ann Surg 1982;;196:297-304.
4 +
Dawson CW, Ledgerwood AM, Rosenberg JC, et al:  Anergy and altered lymphocyte function in the injured patient . Am Surg 1982;;48:397-401.
5 +
Wood JJ, O'Mahony JB, Rodrick ML, et al:  Abnormalities of antibody production after thermal injury: An association with reduced interleukin 2 production . Arch Surg 1986;;121:108-115.
6 +
Davis JM, Dineen P, Gallin JI:  Neutrophil degranulation and abnormal chemotaxis after thermal injury . J Immunol 1980;;124:1467-1471.
7 +
Alexander JW, Ogle CK, Stinnett JD, et al:  A sequential, prospective analysis of immunologic abnormalities and infection following severe thermal injury . Ann Surg 1978;;188:809-816.
8 +
Hansbrough JF, Peterson V, Kortz E, et al:  Postburn immunosuppression in an animal model: Monocyte dysfunction induced by burned tissue . Surgery 1983;;93:415-422.
9 +
Alexander JW, Moncrief JA:  Alterations of the immune response following severe thermal injury . Arch Surg 1966;;93:75-83.
10 +
Baker CC, Miller CL, Trunkey DD:  Predicting fatal sepsis in burn patients . J Trauma 1979;;19:641-648.
11 +
Goodman MG, Weigle WO:  Modulation of lymphocyte activation: Inhibition by an oxidation product of arachidonic acid . J Immunol 1980;;125: 593-600.
12 +
Gualde N, Rabinovitch H, Fredon M, et al:  Effects of 15-hydroperoxyeicosatetraenoic acid on human lymphocyte—sheep erythrocyte rosette formation and response to concanavalin A associated with HLA system . Eur J Immunol 1982;;12:773-777.
13 +
Payan DG, Goetzl EJ:  Specific suppression of human T lymphocyte activation by leukotriene B4 . J Immunol 1983;;131:551-553.
14 +
Ninnemann JL, Stockland AE:  Participation of prostaglandin E in immunosuppression following thermal injury . J Trauma 1984;;24:201-207.
15 +
Ninnemann JL, Condie JT, Davis SE, et al:  Isolation of immunosuppressive serum components following thermal injury . J Trauma 1982;;22: 837-844.
16 +
Constantian MB:  Association of sepsis with an immunosuppressive polypeptide in the serum of burn patients . Ann Surg 1978;;188:209-215.
17 +
Campa M, Benedettini G, De Libero G, et al:  The suppressive activity of T-lymphocytes and serum factors in burned patients . Burns Incl Therm Inj 1981;;8:231-237.
18 +
Deitch EA, Smith BJ:  The effect of blister fluid from thermally injured patients on normal lymphocyte transformation . J Trauma 1983;;23: 106-110.
19 +
Antonacci AC, Calvano SE, Reaves LE, et al:  Autologous and allogeneic mixed-lymphocyte responses following thermal injury in man: The immunomodulatory effects of interleukin-1, interleukin-2, and a prostaglandin inhibitor WY-18251 . Clin Immunol Immunopathol 1984;;30:304-320.
20 +
Grever MR, Thompson VN, Balcerzak SP, et al:  The effect of oxidant stress on human lymphocyte cytotoxicity . Blood 1980;;56:284-288.
21 +
Ayers FC, Warner GL, Smith KL, et al:  Fluorometric quantitation of total and non-protein thiols . Anal Biochem 1986;;154:186-193.
22 +
Hoffeld JT:  Agents which block membrane lipid peroxidation enhance mouse spleen cell immune activities in vitro: Relationship to the enhancing activity of 2-mercaptoethanol . Eur J Immunol 1981;;11:371-376.
23 +
Freed BM, Mozayeni B, Lawrence DA, et al:  Differential inhibition of human T lymphocyte activation by maleimide probes . Cell Immunol 1986;; 101:181-194.
24 +
Hasegawa-Sasaki H, Sasaki T:  Phytohemagglutinin induces rapid degradation of phosphatidylinositol 4,5-biphosphate and transient accumulation of phosphatidic acid and diacylglycerol in a human T lymphoblastoid cell line, CCRF-CEM . Biochim Biophys Acta 1983;;754:305-314.
25 +
Ogawa Y, Taki Y, Kawahara A, et al:  A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes: I. Characterization of a calcium-activated, phospholipid-dependent protein kinase . J Immunol 1981;;127:1369-1374.
26 +
Chaplin DD, Wedner HJ, Parker CW:  Protein phosphorylation in human peripheral blood lymphocytes: Mitogen-induced increases in protein phosphorylation in intact lymphocytes . J Immunol 1980;;124:2390-2398.
27 +
Nishizuka Y:  The role of protein kinase C in cell surface signal transduction and tumor promotion . Nature 1984;;308:693-698.
28 +
Parker CW, Stenson WF, Huber MG, et al:  Formation of thromboxane B2 and hydroxyarachidonic acid in purified human lymphocytes in the presence and absence of PHA . J Immunol 1979;;122:1572-1577.
29 +
Wilson RL:  Organic peroxy free radicals as ultimate agents in oxygen toxicity , in Sies H (ed): Oxidative Stress . London, Academic Press Inc, 1985;, pp 41-72.
30 +
Gutteridge JMC:  The role of superoxide and hydroxy radicals in phospholipid peroxidation catalyzed by iron salts . FEBS Lett 1982;;150:454-458.
31 +
Root RK, Metcalf JA:  H2O2 release from human granulocytes during phagocytosis . J Clin Invest 1977;;60:1266-1279.
32 +
Baldrige CW, Gerard RW:  The extra respiration of phagocytosis . Am J Physiol 1933;;103:235-236.
33 +
Till GO, Hatherrill JR, Tourtellotte WW, et al:  Lipid peroxidation and acute lung injury after thermal trauma to skin: Evidence of a role for hydroxyl radical . Am J Pathol 1985;;119:376-384.
34 +
Rundus C, Peterson VM, Zapata-Sirvent R, et al:  Vitamin E improves cell-mediated immunity in the burned mouse: A preliminary study . Burns 1984;;11:11-15.
35 +
Hiramatsu M, Izawa Y, Hagihara M, et al:  Serum lipid peroxide levels of patients suffering from thermal injury . Burns 1984;;11:111-116.

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1 +
Miller CL, Baker CC:  Changes in lymphocyte activity after thermal injury: The role of suppressor cells . J Clin Invest 1979;;63:202-210.
2 +
Munster AM, Winchurch RA, Birmingham WJ, et al:  Longitudinal assay of lymphocyte responsiveness in patients with major burns . Ann Surg 1980;;192:772-775.
3 +
Mclrvine AJ, O'Mahony JB, Saporoschetz I, et al:  Depressed immune response in burned patients: Use of monoclonal antibodies and functional assays to define the role of suppressor cells . Ann Surg 1982;;196:297-304.
4 +
Dawson CW, Ledgerwood AM, Rosenberg JC, et al:  Anergy and altered lymphocyte function in the injured patient . Am Surg 1982;;48:397-401.
5 +
Wood JJ, O'Mahony JB, Rodrick ML, et al:  Abnormalities of antibody production after thermal injury: An association with reduced interleukin 2 production . Arch Surg 1986;;121:108-115.
6 +
Davis JM, Dineen P, Gallin JI:  Neutrophil degranulation and abnormal chemotaxis after thermal injury . J Immunol 1980;;124:1467-1471.
7 +
Alexander JW, Ogle CK, Stinnett JD, et al:  A sequential, prospective analysis of immunologic abnormalities and infection following severe thermal injury . Ann Surg 1978;;188:809-816.
8 +
Hansbrough JF, Peterson V, Kortz E, et al:  Postburn immunosuppression in an animal model: Monocyte dysfunction induced by burned tissue . Surgery 1983;;93:415-422.
9 +
Alexander JW, Moncrief JA:  Alterations of the immune response following severe thermal injury . Arch Surg 1966;;93:75-83.
10 +
Baker CC, Miller CL, Trunkey DD:  Predicting fatal sepsis in burn patients . J Trauma 1979;;19:641-648.
11 +
Goodman MG, Weigle WO:  Modulation of lymphocyte activation: Inhibition by an oxidation product of arachidonic acid . J Immunol 1980;;125: 593-600.
12 +
Gualde N, Rabinovitch H, Fredon M, et al:  Effects of 15-hydroperoxyeicosatetraenoic acid on human lymphocyte—sheep erythrocyte rosette formation and response to concanavalin A associated with HLA system . Eur J Immunol 1982;;12:773-777.
13 +
Payan DG, Goetzl EJ:  Specific suppression of human T lymphocyte activation by leukotriene B4 . J Immunol 1983;;131:551-553.
14 +
Ninnemann JL, Stockland AE:  Participation of prostaglandin E in immunosuppression following thermal injury . J Trauma 1984;;24:201-207.
15 +
Ninnemann JL, Condie JT, Davis SE, et al:  Isolation of immunosuppressive serum components following thermal injury . J Trauma 1982;;22: 837-844.
16 +
Constantian MB:  Association of sepsis with an immunosuppressive polypeptide in the serum of burn patients . Ann Surg 1978;;188:209-215.
17 +
Campa M, Benedettini G, De Libero G, et al:  The suppressive activity of T-lymphocytes and serum factors in burned patients . Burns Incl Therm Inj 1981;;8:231-237.
18 +
Deitch EA, Smith BJ:  The effect of blister fluid from thermally injured patients on normal lymphocyte transformation . J Trauma 1983;;23: 106-110.
19 +
Antonacci AC, Calvano SE, Reaves LE, et al:  Autologous and allogeneic mixed-lymphocyte responses following thermal injury in man: The immunomodulatory effects of interleukin-1, interleukin-2, and a prostaglandin inhibitor WY-18251 . Clin Immunol Immunopathol 1984;;30:304-320.
20 +
Grever MR, Thompson VN, Balcerzak SP, et al:  The effect of oxidant stress on human lymphocyte cytotoxicity . Blood 1980;;56:284-288.
21 +
Ayers FC, Warner GL, Smith KL, et al:  Fluorometric quantitation of total and non-protein thiols . Anal Biochem 1986;;154:186-193.
22 +
Hoffeld JT:  Agents which block membrane lipid peroxidation enhance mouse spleen cell immune activities in vitro: Relationship to the enhancing activity of 2-mercaptoethanol . Eur J Immunol 1981;;11:371-376.
23 +
Freed BM, Mozayeni B, Lawrence DA, et al:  Differential inhibition of human T lymphocyte activation by maleimide probes . Cell Immunol 1986;; 101:181-194.
24 +
Hasegawa-Sasaki H, Sasaki T:  Phytohemagglutinin induces rapid degradation of phosphatidylinositol 4,5-biphosphate and transient accumulation of phosphatidic acid and diacylglycerol in a human T lymphoblastoid cell line, CCRF-CEM . Biochim Biophys Acta 1983;;754:305-314.
25 +
Ogawa Y, Taki Y, Kawahara A, et al:  A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes: I. Characterization of a calcium-activated, phospholipid-dependent protein kinase . J Immunol 1981;;127:1369-1374.
26 +
Chaplin DD, Wedner HJ, Parker CW:  Protein phosphorylation in human peripheral blood lymphocytes: Mitogen-induced increases in protein phosphorylation in intact lymphocytes . J Immunol 1980;;124:2390-2398.
27 +
Nishizuka Y:  The role of protein kinase C in cell surface signal transduction and tumor promotion . Nature 1984;;308:693-698.
28 +
Parker CW, Stenson WF, Huber MG, et al:  Formation of thromboxane B2 and hydroxyarachidonic acid in purified human lymphocytes in the presence and absence of PHA . J Immunol 1979;;122:1572-1577.
29 +
Wilson RL:  Organic peroxy free radicals as ultimate agents in oxygen toxicity , in Sies H (ed): Oxidative Stress . London, Academic Press Inc, 1985;, pp 41-72.
30 +
Gutteridge JMC:  The role of superoxide and hydroxy radicals in phospholipid peroxidation catalyzed by iron salts . FEBS Lett 1982;;150:454-458.
31 +
Root RK, Metcalf JA:  H2O2 release from human granulocytes during phagocytosis . J Clin Invest 1977;;60:1266-1279.
32 +
Baldrige CW, Gerard RW:  The extra respiration of phagocytosis . Am J Physiol 1933;;103:235-236.
33 +
Till GO, Hatherrill JR, Tourtellotte WW, et al:  Lipid peroxidation and acute lung injury after thermal trauma to skin: Evidence of a role for hydroxyl radical . Am J Pathol 1985;;119:376-384.
34 +
Rundus C, Peterson VM, Zapata-Sirvent R, et al:  Vitamin E improves cell-mediated immunity in the burned mouse: A preliminary study . Burns 1984;;11:11-15.
35 +
Hiramatsu M, Izawa Y, Hagihara M, et al:  Serum lipid peroxide levels of patients suffering from thermal injury . Burns 1984;;11:111-116.

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