Carrageenan: a review of its effects on the immune system

Abstract

Carrageenans (kappa, lambda and iota) are sulphated polysaccharides isolated from marine algae that can markedly suppress immune responses both in vivo and in vitro. Impairment of complement activity and humoral responses to T-dependent antigens, depression of cell-mediated immunity, prolongation of graft survival and potentiation of tumour growth by carrageenans have been reported.

The mechanism responsible for carrageenan-induced immune suppression is believed to be its selective cytopathic effect on macrophages. This property of carrageenan has led to its adoption as a tool for analysing the role of these cells in the induction and expression of immune reactivity. Systemic administration of carrageenan may, however, induce disseminated intravascular coagulation and inflict damage on both the liver and kidney. This is an important consideration in the interpretation of the effects of carrageenan in vivo and precludes its use as a clinical immune suppressant.

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References

  1. [1]

    P. Alexander,The Functions of the Macrophage in Malignant Disease, Ann. Rev. Med.27, 207–224 (1976).

    PubMed  Google Scholar 

  2. [2]

    A.C. Allison, J.S. Harington andM. Birbeck,An Examination of the Cytotoxic Effects of Silica on Macrophages, J. exp. Med.124, 141–153 (1966).

    PubMed  Google Scholar 

  3. [3]

    W. Anderson,Carrageenan. Structure and Biological Activity, Can. J. Pharm. Sci.2, 81–90 (1967).

    Google Scholar 

  4. [4]

    L. Aschheim andS. Raffel,The Immunodepressant Effect of Carrageenin, J. Reticuloendothel. Soc.11, 253–262 (1972).

    PubMed  Google Scholar 

  5. [5]

    L.J. Becker andJ.A. Rudbach Potentiation of Endotoxicity by Carrageenan, Infect. Immun.19, 1099–1100 (1978).

    PubMed  Google Scholar 

  6. [6]

    D.E. Bice, D.G. Gruwell, J.E. Salvaggio andE.O. Hoffmann,Suppression of Primary Immunization by Carrageenan — a Macrophage Toxic Agent, Immunol. Commun.1, 615–625 (1972).

    PubMed  Google Scholar 

  7. [7]

    D. Bice, H.J. Schwartz, W.W. Lake andJ. Salvaggio,The Effect of Carrageenan on the Establishment of Delayed Hypersensitivity, Int. Archs. Allergy41, 628–636 (1971).

    Google Scholar 

  8. [8]

    E. Blitstein-Willinger, G. Schulz andT. Diamantstein,Changes in Thymocyte Reactivity to Lectins Induced by B-Cell Mitogens of the Type of Sulphated Polyanions, Immunology30, 529–535 (1976).

    PubMed  Google Scholar 

  9. [9]

    D.L. Boros andH.J. Schwartz,Effect of Carrageenan on the Development of Hypersensitivity (Schistosoma mansoni Egg) and Foreign Body (Divinyl-benzene Copolymer Beads and Bentonite) Granulomas, Int. Archs. Allergy Appl. Immun.48, 192–202 (1975).

    Google Scholar 

  10. [10]

    T. Borsos., H.J. Rapp andC. Crisler,the Interaction Between Carrageenan and the First Component of Complement, J. Immunol.94, 662–666 (1965).

    PubMed  Google Scholar 

  11. [11]

    J.W.B. Bradfield,Control of Spillover. The Importance of Kupffer Cell Function in Clinical Medicine, Lancetii, 883–886 (1974).

    Google Scholar 

  12. [12]

    R.Y. Calne,Pharmacological Immunosuppression in Clinical Organ Grafting. Observations on Four Agents: Cyclosporin A, Asta 5122 (Cytimun), Lambda Carrageenan and Promethazine Hydrochloride, Clin. exp. Immunol.35, 1–9 (1979).

    PubMed  Google Scholar 

  13. [13]

    R.Y. Calne, K. Rolles, B.M. Herbertson, D.J.G. White andD.P. Smith,Prolonged Survival of Pig Orthotopic Heart Grafts Treated with Cyclosporin A, Lanceti, 1183–1185 (1978).

    Google Scholar 

  14. [14]

    R.Y. Calne, W.J.P. Wall andD.C. Wilkins,Inhibition of Rejection of Canine Renal Allografts by Treatment with Sulphated Polysaccharides, Promethazine Hydrochloride and Azathioprine, IRCS Med. Sci.3, 556 (1975).

    Google Scholar 

  15. [15]

    R.Y. Calne, W.J.P. Wall andD.C. Wilkins,The Individual and Combined Roles of Carrageenan, Promethazine Hydrochloride and Azathioprine as Immunosuppressants in Dogs with Renal Allografts, IRCS Med. Sci.4, 19 (1976).

    Google Scholar 

  16. [16]

    W.J. Catalona, T.L. Ratliff andR.E. McCool,Effects of Carrageenan on Spontaneous and Antibody-Dependent Cell-Mediated Cytotoxicity, Cell. Immunol.40, 1–15 (1978).

    PubMed  Google Scholar 

  17. [17]

    P.J. Catanzaro, H.J. Schwartz andR.C. Graham,Spectrum and Possible Mechanism of Carrageenan Cytotoxicity, Am. J. Path.64, 387–404 (1971).

    PubMed  Google Scholar 

  18. [18]

    D.B. Cater,The Carcinogenic Action of Carrageenin in Rats, Br. J. Cancer15, 607–614 (1961).

    Google Scholar 

  19. [19]

    G. Chaouat andJ.G. Howard,Influence of Reticuloendothelial Blockade on the Induction of Tolerance and Immunity by Polysaccharides, Immunology30, 221–227 (1976).

    PubMed  Google Scholar 

  20. [20]

    G. Cudkowicz andY.P. Yung,Abrogation of Resistance to Foreign Bone Marrow Grafts by Carrageenans. I. Studies with the Anti-macrophage Agent Seakem Carrageenan, J. Immunol.119, 483–487 (1977).

    PubMed  Google Scholar 

  21. [21]

    G.E. Davies,Inhibition of Guinea-Pig Complement in vitro and in vivo by Carrageenin, Immunology6, 561–568 (1963).

    Google Scholar 

  22. [22]

    G.E. Davies,Inhibition of Complement by Carrageenin: Mode of Action, Effect on Allergic Reactions and on Complement of Various Species, Immunology8, 291–299 (1965).

    Google Scholar 

  23. [23]

    M. Di Rosa,Biological Properties of Carrageenan, J. Pharm. Pharmac.24, 89–102 (1972).

    Google Scholar 

  24. [24]

    N.W. Everson, R.L. Stacey andP.R.F. Bell,Effect of λ-Carrageenan on the Survival of Rat Heart Transplants, Transplantation20, 393–394 (1977).

    Google Scholar 

  25. [25]

    J. Ferluga andA.C. Allison,role of Mononuclear Infiltrating Cells in Pathogenesis of Hepatitis, Lancetii, 610–611 (1978).

    Google Scholar 

  26. [26]

    E.F. Fowler, J.G. Simpson andA.W. Thomson,Histological and Ultrastructural Changes Following Carrageenan Injection in the Mouse, J. Path.132, 63–79 (1980).

    PubMed  Google Scholar 

  27. [27]

    E.F. Fowler andA.W. Thomson,Effect of Carrageenan on Activity of the Mononuclear Phagocyte System in the Mouse, Br. J. exp. Path.59, 213–219 (1978).

    Google Scholar 

  28. [28]

    E.F. Fowler andA.W. Thomson,Preservation of Carrageenan-Induced Immune Suppression with Alleviation of Toxicity in Aprotinin-Treated Mice, Int. J. Immunopharmacol.1, 69–72 (1979).

    PubMed  Google Scholar 

  29. [29]

    E.F. Fowler andA.W. Thomson,Serum IgG, IgM and Slow α-Globulin Levels in Carrageenan-Treated Rats, Br. J. exp. Path.60, 353–357 (1979).

    Google Scholar 

  30. [30]

    E.F. Fowler., A.W. Thomson andC.H.W. Horne,Alleviation of Carrageenan-Induced Hepatotoxicity and Acronecrosis by Aprotinin, Br. J. exp. Path.58, 260–267 (1977).

    Google Scholar 

  31. [31]

    N. Hanna andS. Leskowitz,Structural Requirements for in vivo and in vitro Immunogenicity in Hapten-Specific Delayed Hypersensitivity, Cell. Immunol.7, 189–197 (1973).

    PubMed  Google Scholar 

  32. [32]

    S. Ishizaka, S. Otani andS. Morisawa,Effects of Carrageenan on Immune Responses. I. Studies on the Macrophage Dependency of Various Antigens after Treatment with Carrageenan, J. Immunol.118, 1213–1218 (1977).

    PubMed  Google Scholar 

  33. [33]

    A. Janezic, M. Mostarica-Stojkovic andM.L. Luckic.Effects of Carrageenan on the Immune Response to LPS in Rats, Period. biol.81, 133–135 (1979).

    Google Scholar 

  34. [34]

    R. Keller,Promotion of Tumour Growth in vivo by Anti-Macrophage Agents, J. natn. Cancer Inst.57, 1355–1361 (1976).

    Google Scholar 

  35. [35]

    R. Kiessling, P.S. Hochman, O. Haller, G.M. Shearer, H. Wigzell andG. Cudkowicz,Evidence for a Similar or Common Mechanism for Natural Killer Cell Activity and Resistance to Hemopoietic Grafts, Eur. J. Immunol.7, 655–663 (1977).

    PubMed  Google Scholar 

  36. [36]

    C.J. Lawson, D.A. Rees, D.J. Stancioff andN.F. Stanley,Carrageenans. Part VIII. Repeating Structures of Galactan Sulphates from Furcellaria fastigiata, Gigartina canaliculata, Gigartina chamissoi, Gigartina atropurpurea, Ahnfeltia durvillaei, Gymnogongrus furcellatus, Eucheuma cottonii, Eucheuma spinosum, Eucheuma isiforme, Eucheuma uncinatum, Aghardhiella tenera, Pachymenia hymantophora, and Gloiopeltis cervicornis, J. Chem. Soc. 2177–2182 (1973).

  37. [37]

    M.H. Levy andE.F. Wheelock,Effects of Intravenous Silica on Immune and Non-Immune Functions of the Murine Host, J. Immunol.115, 41–48 (1975).

    PubMed  Google Scholar 

  38. [38]

    E. Lotzová, M.T. Gallagher andJ.J. Trentin,Involvement of Macrophages in Genetic Resistance to Bone Marrow Grafts. Studies with Two Specific Antimacrophage Agents, Carrageenan and Silica, Biomedicine22, 387–392 (1975).

    PubMed  Google Scholar 

  39. [39]

    E. Lotzová andE.R. Richie,Promotion of Incidence of Adenovirus Type 12 Transplantable Tumors by Carrageenan, a Specific Anti-Macrophage Agent, J. natn. Cancer Inst.58, 1171–1172 (1977).

    Google Scholar 

  40. [40]

    M.L. Lukić, C. Cowing andS. Leskowitz,Strain Differences in Ease of Tolerance Induction to Bovine γ-Globulin: Dependence on Macrophage Function, J. Immunol.114, 503–506 (1975).

    PubMed  Google Scholar 

  41. [41]

    M.L. Lukić andS. Leskowitz,Tolerance Induction with Bovine γ-Globulin in Mouse Radiation Chimaeras Depends on Macrophages, Nature252, 605–607 (1974).

    PubMed  Google Scholar 

  42. [42]

    I. Miller andA. Stelzner The in vitro and in vivo Effects of Carrageenin on Humoral and Cellular Factors of Natural Resistance, Folia Microbiol.20, 251–260 (1975).

    Google Scholar 

  43. [43]

    S. Nakamura, M. Yoshinaga andH. Hayashi,Interaction Between Lymphocytes and Inflammatory Exudate Cells. II. A Proteolytic Enzyme Released by PMN as a Possible Mediator for Enhancement of Thymocyte Response, J. Immunol.117, 1–6 (1976).

    PubMed  Google Scholar 

  44. [44]

    J.R. Nash, N.W. Everson, R.F.M. Wood andP.R.F. Bell,Effect of Silica and Carrageenan on the Survival of Islet Allografts, Transplantation29, 206–208 (1980).

    PubMed  Google Scholar 

  45. [45]

    D.S. Nelson (Ed.),Immunobiology of the Macrophage (Academic Press, New York and London 1976).

    Google Scholar 

  46. [46]

    M. Nelson andD.S. Nelson,Macrophages and Resistance to Tumours. Influence of Agents Affecting Macrophages and Delayed-Type Hypersensitivity on Resistance to Tumours Inducing Concomitant Immunity, Aust. J. Exp. Biol. Med. Sci.56, 211–223 (1978).

    PubMed  Google Scholar 

  47. [47]

    M. Nelson andD.S. Nelson,Macrophages and Resistance to Tumours. II. Influence of Agents Affecting Macrophages and Delayed-Type Hypersensitivity on Resistance to a Tumour Inducing Specific ‘Sinecomitant’ Immunity: Acquired Resistance as an Expression of Delayed-Type Hypersensitivity, Cancer Immunol. Immunother.4, 101–107 (1978).

    Google Scholar 

  48. [48]

    G. Pawelec andG. Brons,Modification of Lymphocyte Responsiveness in vitro by λ Carrageenan Compared with Colloidal Silica and Depletion of Surface Adherent Cells, Clin. exp. Immunol..31, 426–435 (1978).

    PubMed  Google Scholar 

  49. [49]

    R.G.P., Pugh-Humphreys, C.A. Richardson, A.R. Wilson andW.J. Cruickshank,The Effect of the Macrophage Cytotoxic Agent, Iota Carrageenan on the Growth of Two Transplantable Murine Ascites Tumours, in:the Macrophage and Cancer (Eds. K. James, B. McBride and A Stuart; University of Edinburgh, Edinburgh 1977), pp. 142–154.

    Google Scholar 

  50. [50]

    R.G.P. Pugh-Humphreys. andA.W. Thomson,An Ultrastructural Study of Mononuclear Phagocytes from Iota Carrageenan-Injected Mice, Cytobios24, 211–218 (1979).

    PubMed  Google Scholar 

  51. [51]

    P.C. Quan, J-P.B. Kolb andG. Lespinats,B-Cell Mitogenicity of Carrageenan in Mouse, Cell Immunol.37, 1–13 (1978).

    PubMed  Google Scholar 

  52. [52]

    Z. Ramić, S. Stošić-Grujičić, Z. Pavlović, L. Ejdus andM.M. Simić,Carrageenan Potentiates the Helper Activity of Macrophages in the Response of T Lymphocytes to Mitogens, Period. biol.81, 167–169 (1979).

    Google Scholar 

  53. [53]

    R. Rees,Shapely Polysaccharides, Biochem. J.126 257–273 (1972).

    Google Scholar 

  54. [54]

    A. Rios andR.L. Simmons,Immunosuppressive Effects of Macrophage Lysis. Surg. Forum21, 272–273 (1970).

    PubMed  Google Scholar 

  55. [55]

    A. Rios andR.L. Simmons,Poly-2-vinylpyridine N-Oxide Reverses the Immunosuppressive Effects of Silica and Carrageenan, Transplantation13, 343–345 (1972).

    PubMed  Google Scholar 

  56. [56]

    V.M. Rumjanek andL. Brent,Immunosuppressive Activity of Carrageenan for Cell-Mediated Responses in the Mouse, Transplantation26, 113–118 (1978).

    PubMed  Google Scholar 

  57. [57]

    V.M. Rumjanek, S.R. Watson andV.S. Šljivić,A Re-evaluation of the Role of Macrophages in Carrageenan-Induced Immunosuppression, Immunology33, 423–432 (1977).

    PubMed  Google Scholar 

  58. [58]

    J.E. Sawicki andP.J. Catanzaro,Selective Macrophage Cytotoxicity of Carrageenan in vivo, Int. Archs. appl. Immun.49, 709–714 (1975).

    Google Scholar 

  59. [59]

    H.J. Schwartz andP.J. Catanzaro,The Differential Suppression of Antigen, Lymphokine and Mitogen-Induced Delayed Hypersensitivity-Type Reactions by Carrageenan, Int. Archs. Allergy appl. Immun.44, 409–421 (1973).

    Google Scholar 

  60. [60]

    H.J. Schwartz andR.W. Kellermeyer,Carrageenan and Delayed Hypersensitivity. II. Activation of Hageman Factor by Carrageenan and its Possible Significance, Proc. Soc. Exp. Biol. Med.132, 1021–1024 (1969).

    PubMed  Google Scholar 

  61. [61]

    H.J. Schwartz andS. Leskowitz,The Effect of Carrageenan on Delayed Hypersensitivity Reactions, J. Immunol.103, 87–91 (1969).

    PubMed  Google Scholar 

  62. [62]

    L. Simon andT.L. Jones,Re-evaluation of Carrageenan Cytotoxicity for Macrophages, J. Reticuloendothel. Soc.25, 133–138 (1979).

    PubMed  Google Scholar 

  63. [63]

    R.L. Souhami andJ.W. Bradfield,The Recovery of Hepatic Phagocytosis after Blockade of Kupffer Cells, J. Reticuloendothel. Soc.16, 75–86 (1974).

    PubMed  Google Scholar 

  64. [64]

    W.G. Spector,The Granulomatous Inflammatory Exudate, Int. Rev. exp. Path.8, 1–55 (1969).

    PubMed  Google Scholar 

  65. [65]

    M. Stamenković, S. Stošić-Grujičić andM. M. Simić,Carrageenan-Induced Macrophage Soluble Factors with Co-stimulatory Effects in the Proliferative Response of T Lymphocytes to Mitogens, Period biol.81, 171–173 (1979).

    Google Scholar 

  66. [66]

    P.R.M. Steele, andJ.R. Lowes,A Histopathological Study of the Effects of Intravenously Administered Lambda Carrageenan in the Mouse, with Particular Reference to the Macrophage System, Br. J. exp. Path.60, 358–365 (1979).

    Google Scholar 

  67. [67]

    A.W. Thomson, N. Cruickshank andE.F. Fowler,Enumeration of Fc Receptor-Bearing and Phagocytic Cells within Syngeneic Tumours of C. parvum and Carrageenan Treated Mice, Br. J. Cancer39, 598–602 (1979).

    PubMed  Google Scholar 

  68. [68]

    A.W. Thomson andE.F. Folwer,Potentiation of Tumour Growth by Carrageenan, Transplantation24, 397–400 (1977).

    PubMed  Google Scholar 

  69. [69]

    A.W. Thomson, E.F. Fowler andR.G.P. Pugh-Humphreys,Immunopharmacology of the Macrophage Toxic Agent Carrageenan, Int. J. Immunopharmac.1, 247–261 (1979).

    Google Scholar 

  70. [70]

    A.W. Thomson, R.G. Glover andE.F. Fowler,Mitogenic Effect of the Algal Polygalactan Carrageenan on Cultured Mouse Spleen Cells, Microbios. Lett.6, 145–150 (1977).

    Google Scholar 

  71. [71]

    A.W. Thomson andC.H.W. Horne,Failure of Carrageenan to Affect Graft-Versus-Host Reactivity in the Rat, Transplantation20, 435–437 (1975).

    PubMed  Google Scholar 

  72. [72]

    A.W. Thomson andC.H.W. Horne,Toxicity of Various Carrageenans in the Mouse, Br. J. exp. Path.57, 455–459 (1976).

    Google Scholar 

  73. [73]

    A.W. Thomson, A.R. Wilson, W.J. Cruickshank andC.H.W. Horne,Evaluation of Carrageenan as an Immunosuppressive Agent and Mediator of Intravascular Coagulation, Biomedicine24, 102–106 (1976a).

    PubMed  Google Scholar 

  74. [74]

    A.W. Thomson, A.R. Wilson, W.J. Cruickshank andA.H. Jeffries,Evidence for a Selective Cytotoxic Effect of Carrageenan on Cells of the Immune System in vivo and in vitro, Experientia32, 525–526 (1976b).

    PubMed  Google Scholar 

  75. [75]

    E.V. Turner andR.D. Higginbotham,Carrageenan Induced Alterations of Antigen Distribution and Immune Responses in Mice. J. Reticuloendothel. Soc.22, 545–554 (1977).

    PubMed  Google Scholar 

  76. [76]

    E.R. Unanue,The Regulatory Role of Macrophages in Antigenic Stimulation, Adv. Immunol.15, 95–165 (1972).

    PubMed  Google Scholar 

  77. [77]

    W.J. Wall, R.Y. Calne andD.C. Wilkins,Apparent Antagonism by Heparin of the Immunosuppressant Effect of Carrageenan, Azathioprine and Promethazine in Canine Renal Allografts, IRCS Med. Sci.4, 119 (1976).

    Google Scholar 

  78. [78]

    P.A. Ward andC.G. Cochrane.,Bound Complement and Immunologic Injury of Blood Vessels, J. exp. Med.121, 215–234 (1965).

    PubMed  Google Scholar 

  79. [79]

    D.M. Wong andH.B. Herscowitz Immune Activation by T-Independent Antigens: Lack of Effect of Macrophage Depletion on the Immune Response to TNP-LPS, PVP and Dextran, Immunology37, 765–775 (1979).

    PubMed  Google Scholar 

  80. [80]

    R.L. Wu andR. Kearney,Effect of Carrageenan on the Non-Specific Resistance of Mice to Injected syngeneic Tumour Cells, Alone or in Mixtures, Br. J. Cancer39, 241–246 (1979).

    PubMed  Google Scholar 

  81. [81]

    Y.P. Yung andG. Cudkowicz,Abrogation of Resistance to Foreign Bone Marrow Grafts by Carrageenans. II. Studies with the Anti-Macrophage Agents i, k and λ-Carrageenan, J. Immunol.119, 1310–1315 (1977).

    PubMed  Google Scholar 

  82. [82]

    Y.P. Yung andG. Cudkowicz,Suppression of Cytotoxic T Lymphocytes by Carrageenan-Activated Macrophage-like Cells, J. Immunol.121, 1990–1997 (1978).

    PubMed  Google Scholar 

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Thomson, A.W., Fowler, E.F. Carrageenan: a review of its effects on the immune system. Agents and Actions 11, 265–273 (1981). https://doi.org/10.1007/BF01967625

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Keywords

  • Sulphated
  • Immune Reactivity
  • Immune System
  • Polysaccharide
  • Tumour Growth