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Adverse Effects of Topical Antiglaucoma Medication: I. The Conjunctival Cell Profile

Adverse Effects of Topical Antiglaucoma Medication: I. The Conjunctival Cell Profile Abstract Objective: To determine the effect of various long-term topical antiglaucoma regimens on the cell population profile of the conjunctiva. Methods: Conjunctival biopsy specimens from 124 patients undergoing filtration surgery were assessed quantitatively by light microscopy. Preoperatively, the patients had used a drug for only a brief period (group A; n=28), a β-blocker alone (group B; n=31), a β-blocker in combination with a miotic (group C; n=33), or a combination of β-blocker, miotic, andsympathomimetic (group D; n=32). Results: The conjunctiva in groups A and B was similar. Group C conjunctiva differed, but the changes were most marked in biopsy specimens from patients in group D, where there was a significant decrease in goblet cells (P<.05); increase in pale cells, macrophages, and lymphocytes within the epithelium (P<.001); and increase in fibroblasts (P<.001), macrophages (P<.001), mast cells (P<.05), and lymphocytes (P=.01) in the substantia propria. In addition, the effect of duration of therapy was assessed. Administration of topical medication for more than 3 years was found to increase the numbers of pale cells within the epithelium (P<.05); fibroblasts (P<.05), macrophages (P<.001), lymphocytes (P<.01), and mast cells (P=.001) within the superficial substantia propria; and the numbers of fibroblasts (P=.01) and macrophages (P<.05) within the deep substantia propria. Conclusions: The compared treatment regimens affected the conjunctiva to different degrees, with multipledrug topical therapy exerting the greatest effect on the degree of subclinical inflammation within the conjunctiva. The results also indicated that administration of topical medication, irrespective of type, for 3 years or more induced a significant degree of subclinical inflammation. References 1. Skuta GL, Parrish RK II. Wound healing in glaucoma filtering surgery . Surv Ophthalmol . 1987;32:149-170.Crossref 2. Alvarado JA. The use of a liposome-encapsulated 5-fluoroorotate for glaucoma surgery, I: animal studies . Trans Am Ophthalmol Soc . 1989;87:489-514. 3. Sherwood MB, Grierson I, Millar L, Hitchings RA. Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients . Ophthalmology . 1989;96:327-335.Crossref 4. Wright P. Squamous metaplasia or epidermalization of the conjunctiva as an adverse reaction to topical medication . Trans Ophthalmol Soc U K . 1979;99:244-246. 5. Varga M, Follmann P. Feinstrukturelle Untersuchungen der Bindehautoberfläche nach Langzeitbehandlung mit Timolol . Fortschr Ophthalmol . 1986;83:155-157. 6. Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug . Ophthalmology . 1992;99:1082-1088.Crossref 7. Brandt JD, Wittpenn JR, Katz LJ, Steinmann WN, Spaeth GL. Conjunctival impression cytology in patients with glaucoma using long-term topical medication . Am J Ophthalmol . 1991;112:297-301. 8. Steuhl KP, Knorr M, Frohn A, Thiel H-J. Über den Einfluss antiglaukomatöser Augentropfen auf die Zelldifferenzierung der Konjunktiva . Fortschr Ophthalmol . 1991;88:865-869. 9. Schwab IR, Linberg JV, Gioia VM, Benson WH, Chao GM. Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications . Ophthalmology . 1992;99:197-202.Crossref 10. Abdel-Khalek LMR, Williamson J, Lee WR. Morphological changes in the human conjunctival epithelium, I: in the normal elderly population . Br J Ophthalmol . 1978;62:792-799.Crossref 11. Hitchings RA, Grierson I. Clinico pathological correlation in eyes with failed fistulizing surgery . Trans Ophthalmol Soc U K . 1983;103:84-88. 12. Desjardins DC, Parrish RK, Folberg R, Nevarez J, Heuer DK, Gressel MG. Wound healing after filtering surgery in owl monkeys . Arch Ophthalmol . 1986:104:1835-1839.Crossref 13. Ross R. The fibroblast and wound repair . Biol Rev . 1968;43:51-96.Crossref 14. Regan EF. Scleral cautery with iridectomy, an experimental study . Trans Am Ophthalmol Soc . 1963;61:219-231. 15. Miller MH, Grierson I, Unger WI, Hitchings RA. Wound healing in an animal model of glaucoma fistulizing surgery in the rabbit . Ophthalmic Surg . 1989;20:350-357. 16. Peiffer RL Jr, Lipper S, Merritt JC, Wright W, Jones B. Myofibroblasts in the healing of filtering wounds in rabbit, dog, and cat . Glaucoma . 1981;3:277-280. 17. Reddick R, Merritt JC, Ross G, Avery A, Peiffer RL. Myofibroblasts in filtration operations . Ann Ophthalmol . 1985;17:200-203. 18. Jampel HD, McGuigan LJB, Dunkelberger GR, L'Hernault NL, Quigley HA. Cellular proliferation after experimental glaucoma filtration surgery . Arch Ophthalmol . 1988;106:89-94.Crossref 19. Seetner A, Morin JD. Healing of trabeculectomies in rabbits . Can J Ophthalmol . 1979;14:121-125. 20. Goodman DF, Alvarado JA, Stern W, Heath T, Kramer S. Liposomal incorporated 5-fluoroorotate inhibition of wound healing following posterior lip sclerectomy in the primate . Invest Ophthalmol Vis Sci . 1987;28( (suppl) ):271. Abstract. 21. Williams DE, Nguyen KD, Shapourifar-Tehrani S, Kitada S, Lee DA. Effects of timolol, betaxolol, and levobunolol on human Tenon's fibroblasts in tissue culture . Invest Ophthalmol Vis Sci . 1992;33:2233-2241. 22. Herschler J, Claflin AJ, Fiorentino G. The effect of aqueous humor on the growth of subconjunctival fibroblasts in tissue culture and its implications for glaucoma surgery . Am J Ophthalmol . 1980;89:245-249. 23. Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimacrophage serum . Am J Pathol . 1975;78:71-91. 24. Bryant SM, Fukasawa M, Orita H, Rodgers KE, diZerega GS. Mediation of postsurgical wound healing by macrophages . Prog Clin Biol Res . 1988:266:273-290. 25. Riches DWH. The multiple roles of macrophages in wound healing . In: Clark RAF, Henson PM. The Molecular and Cellular Biology of Wound Repair . New York, NY: Plenum Press; 1988:213-239. 26. Johnston RB. Immunology: monocytes and macrophages . N Engl J Med . 1988;318:747-752.Crossref 27. Leibovich SJ, Wiseman DM. Macrophages, wound repair and angiogenesis . Prog Clin Biol Res . 1988;266:131-145. 28. Wong H, Wahl S. Inflammation and repair . In: Sporn M, Roberts A, eds. Handbook of Experimental Pharmacology, Vol 95/11: Peptide Growth Factors and Their Receptors II . Berlin, Germany: Springer-Verlag; 1990:509-548. 29. Kovacs EJ, Kelley J. Lymphokine regulation of macrophage-derived growth factor secretion following pulmonary injury . Am J Pathol . 1985;121:261-268. 30. Madtes DK, Raines EW, Sakariassen KS, et al. Induction of transforming growth factor-α in activated human alveolar macrophages . Cell . 1988;53:285-293.Crossref 31. Rapolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-α and other growth factors in vivo: analysis by mRNA phenotyping . Science . 1988;241:708-712.Crossref 32. Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF. Transforming growth factor-β reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor . Proc Natl Acad Sci U S A . 1989;86:2229-2233.Crossref 33. Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis . J Exp Med . 1989;170:655-663.Crossref 34. Piguet PF, Collart MA, Grau GE, Sappino A-P, Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis . Nature . 1990;344:245-247.Crossref 35. Fishel RS, Barbul A, Beschorner WE, Wasserkrug HL, Efron G. Lymphocyte participation in wound healing: morphologic assessment using monoclonal antibodies . Ann Surg . 1987;206:25-29.Crossref 36. Barbul A. Role of the T cell-dependent immune system in wound healing . Prog Clin Biol Res . 1988;266:161-175. 37. Regan MC, Barbul A. Regulation of wound healing by the T cell-dependent immune system . In: Janssen H, Rooman R, Robertson JIS, eds. Wound Healing . Petersfield, England: Wrightson Biomedical Publishing Ltd; 1991:21-31. 38. Barbul A, Breslin RJ, Woodyard JP, Wasserkrug HL, Efron G. The effect of in vivo T helper and T suppressor lymphocyte depletion on wound healing . Ann Surg . 1989;209:479-483.Crossref 39. Wahl SM, Allen JB. T lymphocyte-dependent mechanisms of fibrosis . Prog Clin Biol Res . 1988;266:147-160. 40. Roberts AB, Sporn MB, Assoian RK, et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro . Proc Natl Acad Sci U S A . 1986;83:4167-4171.Crossref 41. Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF. Accelerated wound healing of incisional wounds in rats by transforming growth factor-β . Science . 1987;237:1333-1338.Crossref 42. Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta . J Cell Biol . 1987;105:1039-1045.Crossref 43. Azizkhan RG, Azizkhan JC, Zetter BR, Folkman J. Mast cell heparin stimulates migration of capillary endothelial cells in vitro . J Exp Med . 1980;152:931-944.Crossref 44. Irani A-MA, Schwartz LB. Mast cell heterogeneity . Clin Exp Allergy . 1989;19:143-155.Crossref 45. Wasserman SI. Mast cell biology . J Allergy Clin Immunol . 1990;86:590-593.Crossref 46. Gordon JR, Burd PR, Galli SJ. Mast cells as a source of multifunctional cytokines . Immunol Today . 1990;11:458-463.Crossref 47. Stevens RL, Austen KF. Recent advances in the cellular and molecular biology of mast cells . Immunol Today . 1989;10:381-386.Crossref 48. Derous D, de Keizer RJW, de Wolff-Rouendaal D, Soudijn W. Conjunctival keratinisation, an abnormal reaction to an ocular beta-blocker . Acta Ophthalmol . 1989;67:333-338.Crossref 49. Gerstenberger A, Marquardt R. Die Becherzelldichte unter Pilocarpineinfluss . Fortschr Ophthalmol . 1986:83:46-50. 50. Smith DL, Skuta GL, Kincaid MC, Rabbani R, Cruess DF, Kao SF. The effects of glaucoma medications on Tenon's capsule and conjunctiva in the rabbit . Ophthalmic Surg . 1991;22:336-340. 51. Shelly WB, Juhlin L. A reticulo-epithelial system: cutaneous trap for antigens . Trans Assoc Am Phys . 1976;89:245-253. 52. Silberberg-Sinakin I, Fedorko ME, Baer RL, Rosenthal SA, Berezowsky V, Thorbecke GJ. Langerhans cells: target cells in immune complex reactions . Cell Immunol . 1977;32:400-416.Crossref 53. Roitt IM, Brostoff J, Male DK. Cells involved in the immune response . In: van den Berghe L, ed. Immunology . 2nd ed. London, England: Gower Medical Publishing; 1989:2.1-2.18. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

Adverse Effects of Topical Antiglaucoma Medication: I. The Conjunctival Cell Profile

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American Medical Association
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Copyright © 1994 American Medical Association. All Rights Reserved.
ISSN
0003-9950
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1538-3687
DOI
10.1001/archopht.1994.01090230051020
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Abstract

Abstract Objective: To determine the effect of various long-term topical antiglaucoma regimens on the cell population profile of the conjunctiva. Methods: Conjunctival biopsy specimens from 124 patients undergoing filtration surgery were assessed quantitatively by light microscopy. Preoperatively, the patients had used a drug for only a brief period (group A; n=28), a β-blocker alone (group B; n=31), a β-blocker in combination with a miotic (group C; n=33), or a combination of β-blocker, miotic, andsympathomimetic (group D; n=32). Results: The conjunctiva in groups A and B was similar. Group C conjunctiva differed, but the changes were most marked in biopsy specimens from patients in group D, where there was a significant decrease in goblet cells (P<.05); increase in pale cells, macrophages, and lymphocytes within the epithelium (P<.001); and increase in fibroblasts (P<.001), macrophages (P<.001), mast cells (P<.05), and lymphocytes (P=.01) in the substantia propria. In addition, the effect of duration of therapy was assessed. Administration of topical medication for more than 3 years was found to increase the numbers of pale cells within the epithelium (P<.05); fibroblasts (P<.05), macrophages (P<.001), lymphocytes (P<.01), and mast cells (P=.001) within the superficial substantia propria; and the numbers of fibroblasts (P=.01) and macrophages (P<.05) within the deep substantia propria. Conclusions: The compared treatment regimens affected the conjunctiva to different degrees, with multipledrug topical therapy exerting the greatest effect on the degree of subclinical inflammation within the conjunctiva. The results also indicated that administration of topical medication, irrespective of type, for 3 years or more induced a significant degree of subclinical inflammation. References 1. Skuta GL, Parrish RK II. Wound healing in glaucoma filtering surgery . Surv Ophthalmol . 1987;32:149-170.Crossref 2. Alvarado JA. The use of a liposome-encapsulated 5-fluoroorotate for glaucoma surgery, I: animal studies . Trans Am Ophthalmol Soc . 1989;87:489-514. 3. Sherwood MB, Grierson I, Millar L, Hitchings RA. Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients . Ophthalmology . 1989;96:327-335.Crossref 4. Wright P. Squamous metaplasia or epidermalization of the conjunctiva as an adverse reaction to topical medication . Trans Ophthalmol Soc U K . 1979;99:244-246. 5. Varga M, Follmann P. Feinstrukturelle Untersuchungen der Bindehautoberfläche nach Langzeitbehandlung mit Timolol . Fortschr Ophthalmol . 1986;83:155-157. 6. Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug . Ophthalmology . 1992;99:1082-1088.Crossref 7. Brandt JD, Wittpenn JR, Katz LJ, Steinmann WN, Spaeth GL. Conjunctival impression cytology in patients with glaucoma using long-term topical medication . Am J Ophthalmol . 1991;112:297-301. 8. Steuhl KP, Knorr M, Frohn A, Thiel H-J. Über den Einfluss antiglaukomatöser Augentropfen auf die Zelldifferenzierung der Konjunktiva . Fortschr Ophthalmol . 1991;88:865-869. 9. Schwab IR, Linberg JV, Gioia VM, Benson WH, Chao GM. Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications . Ophthalmology . 1992;99:197-202.Crossref 10. Abdel-Khalek LMR, Williamson J, Lee WR. Morphological changes in the human conjunctival epithelium, I: in the normal elderly population . Br J Ophthalmol . 1978;62:792-799.Crossref 11. Hitchings RA, Grierson I. Clinico pathological correlation in eyes with failed fistulizing surgery . Trans Ophthalmol Soc U K . 1983;103:84-88. 12. Desjardins DC, Parrish RK, Folberg R, Nevarez J, Heuer DK, Gressel MG. Wound healing after filtering surgery in owl monkeys . Arch Ophthalmol . 1986:104:1835-1839.Crossref 13. Ross R. The fibroblast and wound repair . Biol Rev . 1968;43:51-96.Crossref 14. Regan EF. Scleral cautery with iridectomy, an experimental study . Trans Am Ophthalmol Soc . 1963;61:219-231. 15. Miller MH, Grierson I, Unger WI, Hitchings RA. Wound healing in an animal model of glaucoma fistulizing surgery in the rabbit . Ophthalmic Surg . 1989;20:350-357. 16. Peiffer RL Jr, Lipper S, Merritt JC, Wright W, Jones B. Myofibroblasts in the healing of filtering wounds in rabbit, dog, and cat . Glaucoma . 1981;3:277-280. 17. Reddick R, Merritt JC, Ross G, Avery A, Peiffer RL. Myofibroblasts in filtration operations . Ann Ophthalmol . 1985;17:200-203. 18. Jampel HD, McGuigan LJB, Dunkelberger GR, L'Hernault NL, Quigley HA. Cellular proliferation after experimental glaucoma filtration surgery . Arch Ophthalmol . 1988;106:89-94.Crossref 19. Seetner A, Morin JD. Healing of trabeculectomies in rabbits . Can J Ophthalmol . 1979;14:121-125. 20. Goodman DF, Alvarado JA, Stern W, Heath T, Kramer S. Liposomal incorporated 5-fluoroorotate inhibition of wound healing following posterior lip sclerectomy in the primate . Invest Ophthalmol Vis Sci . 1987;28( (suppl) ):271. Abstract. 21. Williams DE, Nguyen KD, Shapourifar-Tehrani S, Kitada S, Lee DA. Effects of timolol, betaxolol, and levobunolol on human Tenon's fibroblasts in tissue culture . Invest Ophthalmol Vis Sci . 1992;33:2233-2241. 22. Herschler J, Claflin AJ, Fiorentino G. The effect of aqueous humor on the growth of subconjunctival fibroblasts in tissue culture and its implications for glaucoma surgery . Am J Ophthalmol . 1980;89:245-249. 23. Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimacrophage serum . Am J Pathol . 1975;78:71-91. 24. Bryant SM, Fukasawa M, Orita H, Rodgers KE, diZerega GS. Mediation of postsurgical wound healing by macrophages . Prog Clin Biol Res . 1988:266:273-290. 25. Riches DWH. The multiple roles of macrophages in wound healing . In: Clark RAF, Henson PM. The Molecular and Cellular Biology of Wound Repair . New York, NY: Plenum Press; 1988:213-239. 26. Johnston RB. Immunology: monocytes and macrophages . N Engl J Med . 1988;318:747-752.Crossref 27. Leibovich SJ, Wiseman DM. Macrophages, wound repair and angiogenesis . Prog Clin Biol Res . 1988;266:131-145. 28. Wong H, Wahl S. Inflammation and repair . In: Sporn M, Roberts A, eds. Handbook of Experimental Pharmacology, Vol 95/11: Peptide Growth Factors and Their Receptors II . Berlin, Germany: Springer-Verlag; 1990:509-548. 29. Kovacs EJ, Kelley J. Lymphokine regulation of macrophage-derived growth factor secretion following pulmonary injury . Am J Pathol . 1985;121:261-268. 30. Madtes DK, Raines EW, Sakariassen KS, et al. Induction of transforming growth factor-α in activated human alveolar macrophages . Cell . 1988;53:285-293.Crossref 31. Rapolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-α and other growth factors in vivo: analysis by mRNA phenotyping . Science . 1988;241:708-712.Crossref 32. Pierce GF, Mustoe TA, Lingelbach J, Masakowski VR, Gramates P, Deuel TF. Transforming growth factor-β reverses the glucocorticoid-induced wound-healing deficit in rats: possible regulation in macrophages by platelet-derived growth factor . Proc Natl Acad Sci U S A . 1989;86:2229-2233.Crossref 33. Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis . J Exp Med . 1989;170:655-663.Crossref 34. Piguet PF, Collart MA, Grau GE, Sappino A-P, Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis . Nature . 1990;344:245-247.Crossref 35. Fishel RS, Barbul A, Beschorner WE, Wasserkrug HL, Efron G. Lymphocyte participation in wound healing: morphologic assessment using monoclonal antibodies . Ann Surg . 1987;206:25-29.Crossref 36. Barbul A. Role of the T cell-dependent immune system in wound healing . Prog Clin Biol Res . 1988;266:161-175. 37. Regan MC, Barbul A. Regulation of wound healing by the T cell-dependent immune system . In: Janssen H, Rooman R, Robertson JIS, eds. Wound Healing . Petersfield, England: Wrightson Biomedical Publishing Ltd; 1991:21-31. 38. Barbul A, Breslin RJ, Woodyard JP, Wasserkrug HL, Efron G. The effect of in vivo T helper and T suppressor lymphocyte depletion on wound healing . Ann Surg . 1989;209:479-483.Crossref 39. Wahl SM, Allen JB. T lymphocyte-dependent mechanisms of fibrosis . Prog Clin Biol Res . 1988;266:147-160. 40. Roberts AB, Sporn MB, Assoian RK, et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro . Proc Natl Acad Sci U S A . 1986;83:4167-4171.Crossref 41. Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF. Accelerated wound healing of incisional wounds in rats by transforming growth factor-β . Science . 1987;237:1333-1338.Crossref 42. Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta . J Cell Biol . 1987;105:1039-1045.Crossref 43. Azizkhan RG, Azizkhan JC, Zetter BR, Folkman J. Mast cell heparin stimulates migration of capillary endothelial cells in vitro . J Exp Med . 1980;152:931-944.Crossref 44. Irani A-MA, Schwartz LB. Mast cell heterogeneity . Clin Exp Allergy . 1989;19:143-155.Crossref 45. Wasserman SI. Mast cell biology . J Allergy Clin Immunol . 1990;86:590-593.Crossref 46. Gordon JR, Burd PR, Galli SJ. Mast cells as a source of multifunctional cytokines . Immunol Today . 1990;11:458-463.Crossref 47. Stevens RL, Austen KF. Recent advances in the cellular and molecular biology of mast cells . Immunol Today . 1989;10:381-386.Crossref 48. Derous D, de Keizer RJW, de Wolff-Rouendaal D, Soudijn W. Conjunctival keratinisation, an abnormal reaction to an ocular beta-blocker . Acta Ophthalmol . 1989;67:333-338.Crossref 49. Gerstenberger A, Marquardt R. Die Becherzelldichte unter Pilocarpineinfluss . Fortschr Ophthalmol . 1986:83:46-50. 50. Smith DL, Skuta GL, Kincaid MC, Rabbani R, Cruess DF, Kao SF. The effects of glaucoma medications on Tenon's capsule and conjunctiva in the rabbit . Ophthalmic Surg . 1991;22:336-340. 51. Shelly WB, Juhlin L. A reticulo-epithelial system: cutaneous trap for antigens . Trans Assoc Am Phys . 1976;89:245-253. 52. Silberberg-Sinakin I, Fedorko ME, Baer RL, Rosenthal SA, Berezowsky V, Thorbecke GJ. Langerhans cells: target cells in immune complex reactions . Cell Immunol . 1977;32:400-416.Crossref 53. Roitt IM, Brostoff J, Male DK. Cells involved in the immune response . In: van den Berghe L, ed. Immunology . 2nd ed. London, England: Gower Medical Publishing; 1989:2.1-2.18.

Journal

Archives of OphthalmologyAmerican Medical Association

Published: Nov 1, 1994

References