Skip to main content
NCBI home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1997 Sep 29;352(1359):1377–1384. doi: 10.1098/rstb.1997.0123

Th2-mediated host protective immunity to intestinal nematode infections.

R K Grencis 1
PMCID: PMC1692029  PMID: 9355130

Abstract

Despite many years of study, relatively little is known about the effector mechanisms that operate against intestine-dwelling nematodes. Most of the current understanding comes from studies of laboratory model systems in rodents. It is clear that when an intestinal helminth infection takes place the immune system generates a strong Th2-mediated response, which regulates a variety of responses characteristic of helminth infections such as eosinophilia, intestinal mastocytosis and elevated IgE production. The ability to modulate the host's immune response in vivo with cytokine-specific monoclonal antibodies and recombinant cytokines, together with the use of animals with disruption of key genes involved in the immune response, have provided powerful tools with which to dissect the potential effector mechanisms operating. In the absence of a T-cell compartment the host is unable to expel the parasite. If a Th1-dominated response is generated, protective immunity is almost universally compromised. Thus, it it would appear that some aspect of a Th2-mediated response controls effector mechanisms. Although it is clear that for some infections the mast cell appears to be involved in protection, probably through the generation of a non-specific inflammatory response, how these cells become activated remains unclear. Data from infections in transgenic animals suggest that activation is not through the high-affinity receptor for IgE. Such studies also call into doubt the importance of conventional interactions between effector leucocytes and antibody. There is little evidence to support a protective role for eosinophilia in any system. New data also imply that, although interleukin 4 (IL-4) is generally important (and can exert effects independent of an adaptive immune response), it is not always sufficient to mediate protection; other Th2 cytokines (e.g. IL-13) may warrant closer investigation. It is apparent that a number of potential Th2-controlled effector mechanisms (some of which may be particularly important at mucosal surfaces) remain to be explored. Overall, it is likely that worm expulsion is the result of a combination of multiple mechanisms, some of which are more critical to some species of parasite than to others.

Full Text

The Full Text of this article is available as a PDF (138.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmad A., Wang C. H., Bell R. G. A role for IgE in intestinal immunity. Expression of rapid expulsion of Trichinella spiralis in rats transfused with IgE and thoracic duct lymphocytes. J Immunol. 1991 May 15;146(10):3563–3570. [PubMed] [Google Scholar]
  2. Alizadeh H., Murrell K. D. The intestinal mast cell response to Trichinella spiralis infection in mast cell-deficient w/wv mice. J Parasitol. 1984 Oct;70(5):767–773. [PubMed] [Google Scholar]
  3. Bancroft A. J., Else K. J., Sypek J. P., Grencis R. K. Interleukin-12 promotes a chronic intestinal nematode infection. Eur J Immunol. 1997 Apr;27(4):866–870. doi: 10.1002/eji.1830270410. [DOI] [PubMed] [Google Scholar]
  4. Behnke J. M., Barnard C. J., Wakelin D. Understanding chronic nematode infections: evolutionary considerations, current hypotheses and the way forward. Int J Parasitol. 1992 Nov;22(7):861–907. doi: 10.1016/0020-7519(92)90046-n. [DOI] [PubMed] [Google Scholar]
  5. Behnke J. M., Wahid F. N., Grencis R. K., Else K. J., Ben-Smith A. W., Goyal P. K. Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius): downregulation of specific cytokine secretion (IL-9 and IL-10) correlates with poor mastocytosis and chronic survival of adult worms. Parasite Immunol. 1993 Jul;15(7):415–421. doi: 10.1111/j.1365-3024.1993.tb00626.x. [DOI] [PubMed] [Google Scholar]
  6. Chan M. S., Medley G. F., Jamison D., Bundy D. A. The evaluation of potential global morbidity attributable to intestinal nematode infections. Parasitology. 1994 Sep;109(Pt 3):373–387. doi: 10.1017/s0031182000078410. [DOI] [PubMed] [Google Scholar]
  7. Coffman R. L., Seymour B. W., Hudak S., Jackson J., Rennick D. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science. 1989 Jul 21;245(4915):308–310. doi: 10.1126/science.2787531. [DOI] [PubMed] [Google Scholar]
  8. Crowle P. K., Reed N. D. Rejection of the intestinal parasite Nippostrongylus brasiliensis by mast cell-deficient W/Wv anemic mice. Infect Immun. 1981 Jul;33(1):54–58. doi: 10.1128/iai.33.1.54-58.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Else K. J., Finkelman F. D., Maliszewski C. R., Grencis R. K. Cytokine-mediated regulation of chronic intestinal helminth infection. J Exp Med. 1994 Jan 1;179(1):347–351. doi: 10.1084/jem.179.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Else K. J., Grencis R. K. Antibody-independent effector mechanisms in resistance to the intestinal nematode parasite Trichuris muris. Infect Immun. 1996 Aug;64(8):2950–2954. doi: 10.1128/iai.64.8.2950-2954.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Else K. J., Grencis R. K. Cellular immune responses to the murine nematode parasite Trichuris muris. I. Differential cytokine production during acute or chronic infection. Immunology. 1991 Apr;72(4):508–513. [PMC free article] [PubMed] [Google Scholar]
  12. Else K. J., Hültner L., Grencis R. K. Cellular immune responses to the murine nematode parasite Trichuris muris. II. Differential induction of TH-cell subsets in resistant versus susceptible mice. Immunology. 1992 Feb;75(2):232–237. [PMC free article] [PubMed] [Google Scholar]
  13. Finkelman F. D., Madden K. B., Cheever A. W., Katona I. M., Morris S. C., Gately M. K., Hubbard B. R., Gause W. C., Urban J. F., Jr Effects of interleukin 12 on immune responses and host protection in mice infected with intestinal nematode parasites. J Exp Med. 1994 May 1;179(5):1563–1572. doi: 10.1084/jem.179.5.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Finkelman F. D., Shea-Donohue T., Goldhill J., Sullivan C. A., Morris S. C., Madden K. B., Gause W. C., Urban J. F., Jr Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Annu Rev Immunol. 1997;15:505–533. doi: 10.1146/annurev.immunol.15.1.505. [DOI] [PubMed] [Google Scholar]
  15. Galli S. J., Zsebo K. M., Geissler E. N. The kit ligand, stem cell factor. Adv Immunol. 1994;55:1–96. doi: 10.1016/s0065-2776(08)60508-8. [DOI] [PubMed] [Google Scholar]
  16. Garside P., Grencis R. K., Mowat A. M. T lymphocyte dependent enteropathy in murine Trichinella spiralis infection. Parasite Immunol. 1992 Mar;14(2):217–225. doi: 10.1111/j.1365-3024.1992.tb00462.x. [DOI] [PubMed] [Google Scholar]
  17. Ghildyal N., McNeil H. P., Gurish M. F., Austen K. F., Stevens R. L. Transcriptional regulation of the mucosal mast cell-specific protease gene, MMCP-2, by interleukin 10 and interleukin 3. J Biol Chem. 1992 Apr 25;267(12):8473–8477. [PubMed] [Google Scholar]
  18. Gordon J. R., Burd P. R., Galli S. J. Mast cells as a source of multifunctional cytokines. Immunol Today. 1990 Dec;11(12):458–464. doi: 10.1016/0167-5699(90)90176-a. [DOI] [PubMed] [Google Scholar]
  19. Grencis R. K., Hültner L., Else K. J. Host protective immunity to Trichinella spiralis in mice: activation of Th cell subsets and lymphokine secretion in mice expressing different response phenotypes. Immunology. 1991 Oct;74(2):329–332. [PMC free article] [PubMed] [Google Scholar]
  20. Grencis R. K., Riedlinger J., Wakelin D. L3T4-positive T lymphoblasts are responsible for transfer of immunity to Trichinella spiralis in mice. Immunology. 1985 Oct;56(2):213–218. [PMC free article] [PubMed] [Google Scholar]
  21. Harari Y., Russell D. A., Castro G. A. Anaphylaxis-mediated epithelial Cl- secretion and parasite rejection in rat intestine. J Immunol. 1987 Feb 15;138(4):1250–1255. [PubMed] [Google Scholar]
  22. Herndon F. J., Kayes S. G. Depletion of eosinophils by anti-IL-5 monoclonal antibody treatment of mice infected with Trichinella spiralis does not alter parasite burden or immunologic resistance to reinfection. J Immunol. 1992 Dec 1;149(11):3642–3647. [PubMed] [Google Scholar]
  23. Horii Y., Khan A. I., Nawa Y. Persistent infection of Strongyloides venezuelensis and normal expulsion of Nippostrongylus brasiliensis in Mongolian gerbils, Meriones unguiculatus, with reference to the cellular responses in the intestinal mucosa. Parasite Immunol. 1993 Mar;15(3):175–179. doi: 10.1111/j.1365-3024.1993.tb00597.x. [DOI] [PubMed] [Google Scholar]
  24. Hültner L., Druez C., Moeller J., Uyttenhove C., Schmitt E., Rüde E., Dörmer P., Van Snick J. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol. 1990 Jun;20(6):1413–1416. doi: 10.1002/eji.1830200632. [DOI] [PubMed] [Google Scholar]
  25. Ishikawa N., Horii Y., Nawa Y. Immune-mediated alteration of the terminal sugars of goblet cell mucins in the small intestine of Nippostrongylus brasiliensis-infected rats. Immunology. 1993 Feb;78(2):303–307. [PMC free article] [PubMed] [Google Scholar]
  26. Jacobson R. H., Reed N. D., Manning D. D. Expulsion of Nippostrongylus brasiliensis from mice lacking antibody production potential. Immunology. 1977 Jun;32(6):867–874. [PMC free article] [PubMed] [Google Scholar]
  27. Jarrett E., Bazin H. Elevation of total serum IgE in rats following helminth parasite infection. Nature. 1974 Oct 18;251(5476):613–614. doi: 10.1038/251613a0. [DOI] [PubMed] [Google Scholar]
  28. Katona I. M., Urban J. F., Jr, Finkelman F. D. The role of L3T4+ and Lyt-2+ T cells in the IgE response and immunity to Nippostrongylus brasiliensis. J Immunol. 1988 May 1;140(9):3206–3211. [PubMed] [Google Scholar]
  29. Khan W. I., Abe T., Ishikawa N., Nawa Y., Yoshimura K. Reduced amount of intestinal mucus by treatment with anti-CD4 antibody interferes with the spontaneous cure of Nippostrongylus brasiliensis-infection in mice. Parasite Immunol. 1995 Sep;17(9):485–491. doi: 10.1111/j.1365-3024.1995.tb00919.x. [DOI] [PubMed] [Google Scholar]
  30. Kopf M., Le Gros G., Bachmann M., Lamers M. C., Bluethmann H., Köhler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993 Mar 18;362(6417):245–248. doi: 10.1038/362245a0. [DOI] [PubMed] [Google Scholar]
  31. Koyama K., Tamauchi H., Ito Y. The role of CD4+ and CD8+ T cells in protective immunity to the murine nematode parasite Trichuris muris. Parasite Immunol. 1995 Mar;17(3):161–165. doi: 10.1111/j.1365-3024.1995.tb01018.x. [DOI] [PubMed] [Google Scholar]
  32. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  33. Lawrence R. A., Gray C. A., Osborne J., Maizels R. M. Nippostrongylus brasiliensis: cytokine responses and nematode expulsion in normal and IL-4-deficient mice. Exp Parasitol. 1996 Oct;84(1):65–73. doi: 10.1006/expr.1996.0090. [DOI] [PubMed] [Google Scholar]
  34. Madden K. B., Urban J. F., Jr, Ziltener H. J., Schrader J. W., Finkelman F. D., Katona I. M. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J Immunol. 1991 Aug 15;147(4):1387–1391. [PubMed] [Google Scholar]
  35. Maizels R. M., Bundy D. A., Selkirk M. E., Smith D. F., Anderson R. M. Immunological modulation and evasion by helminth parasites in human populations. Nature. 1993 Oct 28;365(6449):797–805. doi: 10.1038/365797a0. [DOI] [PubMed] [Google Scholar]
  36. Manson-Smith D. F., Bruce R. G., Parrott D. M. Villous atrophy and expulsion of intestinal Trichinella spiralis are mediated by T cells. Cell Immunol. 1979 Oct;47(2):285–292. doi: 10.1016/0008-8749(79)90338-1. [DOI] [PubMed] [Google Scholar]
  37. Miller H. R. Gastrointestinal mucus, a medium for survival and for elimination of parasitic nematodes and protozoa. Parasitology. 1987;94 (Suppl):S77–100. doi: 10.1017/s0031182000085838. [DOI] [PubMed] [Google Scholar]
  38. Miller H. R., Nawa Y. Nippostrongylus brasiliensis: intestinal goblet-cell response in adoptively immunized rats. Exp Parasitol. 1979 Feb;47(1):81–90. doi: 10.1016/0014-4894(79)90010-9. [DOI] [PubMed] [Google Scholar]
  39. Moqbel R., Wakelin D., MacDonald A. J., King S. J., Grencis R. K., Kay A. B. Release of leukotrienes during rapid expulsion of Trichinella spiralis from immune rats. Immunology. 1987 Mar;60(3):425–430. [PMC free article] [PubMed] [Google Scholar]
  40. Morawetz R. A., Gabriele L., Rizzo L. V., Noben-Trauth N., Kühn R., Rajewsky K., Müller W., Doherty T. M., Finkelman F., Coffman R. L. Interleukin (IL)-4-independent immunoglobulin class switch to immunoglobulin (Ig)E in the mouse. J Exp Med. 1996 Nov 1;184(5):1651–1661. doi: 10.1084/jem.184.5.1651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  42. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  43. Mowat A. M. Antibodies to IFN-gamma prevent immunologically mediated intestinal damage in murine graft-versus-host reaction. Immunology. 1989 Sep;68(1):18–23. [PMC free article] [PubMed] [Google Scholar]
  44. Nawa Y., Ishikawa N., Tsuchiya K., Horii Y., Abe T., Khan A. I., Bing-Shi, Itoh H., Ide H., Uchiyama F. Selective effector mechanisms for the expulsion of intestinal helminths. Parasite Immunol. 1994 Jul;16(7):333–338. doi: 10.1111/j.1365-3024.1994.tb00358.x. [DOI] [PubMed] [Google Scholar]
  45. Ogilvie B. M., Jones V. E. Passive protection with cells or antiserum against Nippostronglylus brasiliensis in the rat. Parasitology. 1968 Nov;58(4):939–949. doi: 10.1017/s0031182000069705. [DOI] [PubMed] [Google Scholar]
  46. Ogilvie B. M., Love R. J. Co-operation between antibodies and cells in immunity to a nematode parasite. Transplant Rev. 1974;19(0):147–169. doi: 10.1111/j.1600-065x.1974.tb00131.x. [DOI] [PubMed] [Google Scholar]
  47. Perdue M. H., Ramage J. K., Burget D., Marshall J., Masson S. Intestinal mucosal injury is associated with mast cell activation and leukotriene generation during Nippostrongylus-induced inflammation in the rat. Dig Dis Sci. 1989 May;34(5):724–731. doi: 10.1007/BF01540344. [DOI] [PubMed] [Google Scholar]
  48. Pritchard D. I. Immunity to helminths: is too much IgE parasite--rather than host-protective? Parasite Immunol. 1993 Jan;15(1):5–9. doi: 10.1111/j.1365-3024.1993.tb00566.x. [DOI] [PubMed] [Google Scholar]
  49. Puddington L., Olson S., Lefrançois L. Interactions between stem cell factor and c-Kit are required for intestinal immune system homeostasis. Immunity. 1994 Dec;1(9):733–739. doi: 10.1016/s1074-7613(94)80015-4. [DOI] [PubMed] [Google Scholar]
  50. Ramaswamy K., Goodman R. E., Bell R. G. Cytokine profile of protective anti-Trichinella spiralis CD4+ OX22- and non-protective CD4+ OX22+ thoracic duct cells in rats: secretion of IL-4 alone does not determine protective capacity. Parasite Immunol. 1994 Aug;16(8):435–445. doi: 10.1111/j.1365-3024.1994.tb00371.x. [DOI] [PubMed] [Google Scholar]
  51. Ramaswamy K., Hakimi J., Bell R. G. Evidence for an interleukin 4-inducible immunoglobulin E uptake and transport mechanism in the intestine. J Exp Med. 1994 Nov 1;180(5):1793–1803. doi: 10.1084/jem.180.5.1793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rennick D. M., Lee F. D., Yokota T., Arai K. I., Cantor H., Nabel G. J. A cloned MCGF cDNA encodes a multilineage hematopoietic growth factor: multiple activities of interleukin 3. J Immunol. 1985 Feb;134(2):910–914. [PubMed] [Google Scholar]
  53. SYMONS L. E. KINETICS OF THE EPITHELIAL CELLS, AND MORPHOLOGY OF VILLI AND CRYPTS IN THE JEJUNUM OF THE RAT INFECTED BY THE NEMATODE NIPPOSTRONGYLUS BRASILIENSIS. Gastroenterology. 1965 Aug;49:158–168. [PubMed] [Google Scholar]
  54. Scudamore C. L., Thornton E. M., McMillan L., Newlands G. F., Miller H. R. Release of the mucosal mast cell granule chymase, rat mast cell protease-II, during anaphylaxis is associated with the rapid development of paracellular permeability to macromolecules in rat jejunum. J Exp Med. 1995 Dec 1;182(6):1871–1881. doi: 10.1084/jem.182.6.1871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Symons L. E. Epithelia cell mitosis and morphology in worm-free regions of the intestines of the rat infected by Nippostrongylus brasiliensis. J Parasitol. 1978 Oct;64(5):958–959. [PubMed] [Google Scholar]
  56. Takai T., Li M., Sylvestre D., Clynes R., Ravetch J. V. FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell. 1994 Feb 11;76(3):519–529. doi: 10.1016/0092-8674(94)90115-5. [DOI] [PubMed] [Google Scholar]
  57. Tuohy M., Lammas D. A., Wakelin D., Huntley J. F., Newlands G. F., Miller H. R. Functional correlations between mucosal mast cell activity and immunity to Trichinella spiralis in high and low responder mice. Parasite Immunol. 1990 Nov;12(6):675–685. doi: 10.1111/j.1365-3024.1990.tb00996.x. [DOI] [PubMed] [Google Scholar]
  58. Urban J. F., Jr, Katona I. M., Paul W. E., Finkelman F. D. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5513–5517. doi: 10.1073/pnas.88.13.5513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Urban J. F., Jr, Maliszewski C. R., Madden K. B., Katona I. M., Finkelman F. D. IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J Immunol. 1995 May 1;154(9):4675–4684. [PubMed] [Google Scholar]
  60. Wahid F. N., Behnke J. M., Grencis R. K., Else K. J., Ben-Smith A. W. Immunological relationships during primary infection with Heligmosomoides polygyrus: Th2 cytokines and primary response phenotype. Parasitology. 1994 May;108(Pt 4):461–471. doi: 10.1017/s0031182000076022. [DOI] [PubMed] [Google Scholar]
  61. Wahid F. N., Behnke J. M. Immunological relationships during primary infection with Heligmosomoides polygyrus. Regulation of fast response phenotype by H-2 and non-H-2 genes. Parasitology. 1993 Sep;107(Pt 3):343–350. doi: 10.1017/s0031182000079312. [DOI] [PubMed] [Google Scholar]
  62. Wakelin D. Immunity to intestinal parasites. Nature. 1978 Jun 22;273(5664):617–620. doi: 10.1038/273617a0. [DOI] [PubMed] [Google Scholar]
  63. Woodbury R. G., Miller H. R., Huntley J. F., Newlands G. F., Palliser A. C., Wakelin D. Mucosal mast cells are functionally active during spontaneous expulsion of intestinal nematode infections in rat. 1984 Nov 29-Dec 5Nature. 312(5993):450–452. doi: 10.1038/312450a0. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES