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June 28, 1995, Vol 273, No. 24 >
ARTICLE | June 28, 1995

T-Helper 1-Type Immunity to Trophoblast in Women With Recurrent Spontaneous Abortion FREE

Joseph A. Hill, MD; Katalin Polgar, PhD; Deborah J. Anderson, PhD
[+] Author Affiliations

Reprint requests to Fearing Research Laboratory, 250 Longwood Ave, Room 204, Boston, MA 02115 (Dr Hill).


JAMA. 1995;273(24):1933-1936. doi:10.1001/jama.1995.03520480053039
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Article
References

Objective.  —To test the hypothesis that peripheral blood mononuclear cells in women with unexplained recurrent abortion (URA) produce T-helper 1 (TH1)—type cytokines in response to trophoblast antigens.

Design.  —Cohort study.

Setting.  —Medical center.

Participants.  —A total of 244 women with URA, 13 reproductively normal parous control women, and 10 men.

Main Outcome Measures.  —Supernatants from trophoblast-activated peripheral blood mononuclear cells from all participants were tested for toxic effects on mouse embryos and by enzyme-linked immunosorbent assay (ELISA) for interferon gamma (IFN-γ). Supernatants from 20 URA patients with embryotoxic activity and IFN-γ, 13 reproductively normal parous women, and 10 men were further tested by ELISA for other TH1-type cytokines (interleukin-2 [IL-2], tumor necrosis factor—β [TNF-β]), TH2-type cytokines (IL-4, IL-10), and TNF-α.

Results.  —Embryotoxic activity was detected in supernatants from 160 of 244 URA patients and in none of the controls. Interferon gamma was detected in supernatants from 125 of 244 URA patients and was significantly associated with embryotoxicity (121 of 160 supernatants with embryotoxicity vs four of 84 supernatants without embryotoxicity [P<.001]). Of 20 supernatants from patients chosen for further study, all were positive for TNF-α, 17 for TNF-β, two for IL-10, and one for IL-4. No cytokines were detected in supernatants from unstimulated or red blood cell membrane—activated cells of women with URA. In contrast, trophoblast-activated lymphocyte supernatants from reproductively normal women and men neither were embryotoxic nor contained TH1-type cytokines, but most contained the TH2-type cytokine IL-10. Three supernatants from reproductively normal women also contained IL-4.

Conclusion.  —Whereas TH1-type immunity to trophoblast is associated with URA and may play a role in reproductive failure, TH2-type immunity may be a natural response to trophoblast contributing to successful pregnancy.(JAMA. 1995;273:1933-1936)

REFERENCES

1 +
Mosmann TR, Cherwinski HM, Bond MW, Giedlin MA, Coffman RL.  Two types of murine helper T cell clones, I: definition according to profiles of lymphokine activities and secreted proteins. J Immunol . 1986;;136:2348-2357.
2 +
Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR.  Two types of mouse helper T cell clones, III: further differences in lymphokine synthesis between TH1 and TH2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med . 1987;; 166:1229-1244.
3 +
Kurt-Jones EA, Hamberg S, Ohara J, Paul WE, Abbas AK.  Heterogeneity of helper/inducer T lymphocytes, I: lymphokine production and lymphokine responsiveness. J Exp Med . 1987;;166:1774-1787.
4 +
Cher DJ, Mosmann TR.  Two types of murine helper T cell clones, II: delayed-type hypersensitivity is mediated by TH1 clones. J Immunol . 1987;; 138:3688-3694.
5 +
Mosmann TR, Coffman RL.  TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol . 1989;;7:145-173.
6 +
Mosmann TR, Coffman RL.  Two types of mouse helper T cell clone: implications for immune regulation. Immunol Today . 1987;;8:223-227.
7 +
Abbas AK, Urioste S, Collins TL, Boom WH.  Heterogeneity of helper/inducer T lymphocytes, IV: stimulation of resting and activated B cells by TH1 and TH2 clones. J Immunol . 1990;;144:2031-2037.
8 +
Powrie F, Coffman RL.  Cytokine regulation of T cell function: potential for therapeutic intervention. Immunol Today . 1993;;14:270-274.
9 +
Mosmann TR, Coffman RL.  Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol . 1989;;46:11.
10 +
Romagnani S.  Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol . 1992;;4:279-285.
11 +
Romagnani S.  Human TH1 and TH2 subsets: doubt no more. Immunol Today . 1991;;8:256-257.
12 +
Hill JA, Polgar K, Harlow BL, Anderson DJ.  Evidence of embryo-and-trophoblast-toxic cellular immune response(s) in women with recurrent spontaneous abortion. Am J Obstet Gynecol . 1992;;166: 1044-1052.
13 +
Ecker JL, Laufer MR, Hill JA.  Measurement of embryotoxic factors is predictive of pregnancy outcome in women with a history of recurrent abortion. Obstet Gynecol . 1993;;81:84-87.
14 +
Yamada H, Polgar K, Hill JA.  Cell-mediated immunity to trophoblast antigens in women with recurrent spontaneous abortion. Am J Obstet Gynecol . 1994;;170:1339-1344.
15 +
Hill JA, Haimovici F, Anderson DJ.  Products of activated lymphocytes and macrophages inhibit mouse embryo development in vitro. J Immunol . 1987;;132:2250-2254.
16 +
Haimovici F, Hill JA, Anderson DJ.  The effects of soluble products of activated lymphocytes and macrophages on blastocyst implantation events in vitro. Biol Reprod . 1991;;44:69-75.
17 +
Berkowitz RS, Hill JA, Kurtz CB, Anderson DJ.  Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro. Am J Obstet Gynecol . 1988;;158:199-203.
18 +
Chaouat G, Menu E, Clark D, Dy M, Minkowski M, Wegmann TG.  Control of fetal survival in CBA × DBA/2 mice by lymphokine therapy. J Reprod Fertil . 1990;;89:447-452.
19 +
Bulmer JN, Johnson PM.  Immunohistological characterization of the decidual leukocyte infiltrate related to endometrial gland epithelium in early human pregnancy. Immunology . 1985;;5:35.
20 +
Kabawat SE, Mostaoufi-Zedeh M, Driscoll SG, Bhan AK.  Implantation site in normal pregnancy: a study with monoclonal antibodies. Am J Pathol . 1985;;118:76-84.
21 +
Bulmer JN.  Immunopathology of pregnancy. Baillieres Clin Immunol Allerg . 1988;;2:697-734.
22 +
Hill JA, Anderson DJ.  Cell-mediated immune mechanisms in recurrent spontaneous abortion.  In: Talwar GP, ed. Contraceptive Research for Today and the Nineties . New York, NY: Springer-Verlag NY Inc; 1988;:171-179.
23 +
Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG.  Synthesis of T-helper 2-type cytokines at the maternal-fetal interface. J Immunol . 1993;;151:4562-4573.
24 +
Berkowitz RS, Alberti OJ, Hunter NJ, et al.  Localization of stage-specific embryonic antigens in hydatiform mole, normal placenta and gestational choriocarcinoma. Gynecol Oncol . 1985;;1:70-77.
25 +
Berkowitz RS, Umpiere SA, Goldstein DP, Anderson DJ.  Cross-reactivity of monoclonal antibodies against lymphocyte markers with trophoblast cells of normal placenta, hydatiform mole and gestational choriocarcinoma. Gynecol. Oncol . 1988;; 29:94-100.
26 +
Loke YW.  Human trophoblast in culture.  In: Loke YW, Whyte A, eds. Biology of Trophoblast . New York, NY: Elsevier Science Publishing Co Inc; 1983;:663-701.
27 +
Billington WD.  Maternal-fetal interactions in normal human pregnancy. Baillieres Clin Immunol Allerg . 1988;;2:527-549.
28 +
Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMarrs R.  A class I antigen, HLA-G, expressed in human trophoblasts. Science . 1990;; 248:220-223.
29 +
Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S.  Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen specific proliferation and cytokine production. J Immunol . 1993;;150:353-360.
30 +
Tite JP, Powell MB, Ruddle NH.  Protein antigen specific Ia-restricated cytolytic T cells: analysis of frequency, target cell susceptibility, and mechanism of cytolysis. J Immunol . 1984;;135:25.
31 +
Fiorentino DF, Bond MW, Mosmann TR.  Two types of mouse T helper cell, IV: TH2 clones secrete a factor that inhibits cytokine production by TH1 clones. J Exp Med . 1989;;170:2081.
32 +
Mosmann TR, Moore KW.  The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today . 1991;;12:49.
33 +
Maggi E, Parronchi P, Monetti R, et al.  Reciprocal regulatory effects of IFN-gamma and IL-4 in vitro development of human Th-1 and Th-2 clones. J Immunol . 1992;;148:2142-2147.
34 +
Gajewski TF, Schell SR, Fitch FW.  Evidence implicating utilization of different T cell receptor— associated signalling of pathways by TH1 and TH2 clones. J Immunol . 1990;;144:4110-4120.
35 +
Williams ME, Lichtman AH, Abbas AK.  Anti-CD3 antibody induces unresponsiveness to IL-2 in TH1 clones but not in TH2 clones. J Immunol . 1990;; 144:1208-1214.
36 +
Fathman CG, Myers BD.  Cyclosporin therapy for autoimmune disease. N Engl J Med . 1992;;326: 1693-1695.
37 +
Hricik DE, Almani WY, Strom TB.  Trends in the use of glucocorticoids in renal transplantation. Transplantation . 1994;;57:979-989.
38 +
Miller A, Lider O, Roberts AB, Spron MB, Weiner HL.  Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen specific triggering. Proc Natl Acad Sci U S A . 1992;;89:421-425.
39 +
Weiner HL, Mackin GA, Matsui M, et al.  Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science . 1993;;259:1321-1324.
40 +
Thorbecke GJ, Shab R, Leu CH, Juruvilla AP, Hardison AM, Palladino MA.  Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci USA . 1992;;89:7375-7379.
41 +
Dwyer JM.  Manipulating the immune system with immune globulin. N Engl J Med . 1992;;326: 107-116.

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1 +
Mosmann TR, Cherwinski HM, Bond MW, Giedlin MA, Coffman RL.  Two types of murine helper T cell clones, I: definition according to profiles of lymphokine activities and secreted proteins. J Immunol . 1986;;136:2348-2357.
2 +
Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR.  Two types of mouse helper T cell clones, III: further differences in lymphokine synthesis between TH1 and TH2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med . 1987;; 166:1229-1244.
3 +
Kurt-Jones EA, Hamberg S, Ohara J, Paul WE, Abbas AK.  Heterogeneity of helper/inducer T lymphocytes, I: lymphokine production and lymphokine responsiveness. J Exp Med . 1987;;166:1774-1787.
4 +
Cher DJ, Mosmann TR.  Two types of murine helper T cell clones, II: delayed-type hypersensitivity is mediated by TH1 clones. J Immunol . 1987;; 138:3688-3694.
5 +
Mosmann TR, Coffman RL.  TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol . 1989;;7:145-173.
6 +
Mosmann TR, Coffman RL.  Two types of mouse helper T cell clone: implications for immune regulation. Immunol Today . 1987;;8:223-227.
7 +
Abbas AK, Urioste S, Collins TL, Boom WH.  Heterogeneity of helper/inducer T lymphocytes, IV: stimulation of resting and activated B cells by TH1 and TH2 clones. J Immunol . 1990;;144:2031-2037.
8 +
Powrie F, Coffman RL.  Cytokine regulation of T cell function: potential for therapeutic intervention. Immunol Today . 1993;;14:270-274.
9 +
Mosmann TR, Coffman RL.  Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol . 1989;;46:11.
10 +
Romagnani S.  Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol . 1992;;4:279-285.
11 +
Romagnani S.  Human TH1 and TH2 subsets: doubt no more. Immunol Today . 1991;;8:256-257.
12 +
Hill JA, Polgar K, Harlow BL, Anderson DJ.  Evidence of embryo-and-trophoblast-toxic cellular immune response(s) in women with recurrent spontaneous abortion. Am J Obstet Gynecol . 1992;;166: 1044-1052.
13 +
Ecker JL, Laufer MR, Hill JA.  Measurement of embryotoxic factors is predictive of pregnancy outcome in women with a history of recurrent abortion. Obstet Gynecol . 1993;;81:84-87.
14 +
Yamada H, Polgar K, Hill JA.  Cell-mediated immunity to trophoblast antigens in women with recurrent spontaneous abortion. Am J Obstet Gynecol . 1994;;170:1339-1344.
15 +
Hill JA, Haimovici F, Anderson DJ.  Products of activated lymphocytes and macrophages inhibit mouse embryo development in vitro. J Immunol . 1987;;132:2250-2254.
16 +
Haimovici F, Hill JA, Anderson DJ.  The effects of soluble products of activated lymphocytes and macrophages on blastocyst implantation events in vitro. Biol Reprod . 1991;;44:69-75.
17 +
Berkowitz RS, Hill JA, Kurtz CB, Anderson DJ.  Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro. Am J Obstet Gynecol . 1988;;158:199-203.
18 +
Chaouat G, Menu E, Clark D, Dy M, Minkowski M, Wegmann TG.  Control of fetal survival in CBA × DBA/2 mice by lymphokine therapy. J Reprod Fertil . 1990;;89:447-452.
19 +
Bulmer JN, Johnson PM.  Immunohistological characterization of the decidual leukocyte infiltrate related to endometrial gland epithelium in early human pregnancy. Immunology . 1985;;5:35.
20 +
Kabawat SE, Mostaoufi-Zedeh M, Driscoll SG, Bhan AK.  Implantation site in normal pregnancy: a study with monoclonal antibodies. Am J Pathol . 1985;;118:76-84.
21 +
Bulmer JN.  Immunopathology of pregnancy. Baillieres Clin Immunol Allerg . 1988;;2:697-734.
22 +
Hill JA, Anderson DJ.  Cell-mediated immune mechanisms in recurrent spontaneous abortion.  In: Talwar GP, ed. Contraceptive Research for Today and the Nineties . New York, NY: Springer-Verlag NY Inc; 1988;:171-179.
23 +
Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG.  Synthesis of T-helper 2-type cytokines at the maternal-fetal interface. J Immunol . 1993;;151:4562-4573.
24 +
Berkowitz RS, Alberti OJ, Hunter NJ, et al.  Localization of stage-specific embryonic antigens in hydatiform mole, normal placenta and gestational choriocarcinoma. Gynecol Oncol . 1985;;1:70-77.
25 +
Berkowitz RS, Umpiere SA, Goldstein DP, Anderson DJ.  Cross-reactivity of monoclonal antibodies against lymphocyte markers with trophoblast cells of normal placenta, hydatiform mole and gestational choriocarcinoma. Gynecol. Oncol . 1988;; 29:94-100.
26 +
Loke YW.  Human trophoblast in culture.  In: Loke YW, Whyte A, eds. Biology of Trophoblast . New York, NY: Elsevier Science Publishing Co Inc; 1983;:663-701.
27 +
Billington WD.  Maternal-fetal interactions in normal human pregnancy. Baillieres Clin Immunol Allerg . 1988;;2:527-549.
28 +
Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMarrs R.  A class I antigen, HLA-G, expressed in human trophoblasts. Science . 1990;; 248:220-223.
29 +
Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S.  Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen specific proliferation and cytokine production. J Immunol . 1993;;150:353-360.
30 +
Tite JP, Powell MB, Ruddle NH.  Protein antigen specific Ia-restricated cytolytic T cells: analysis of frequency, target cell susceptibility, and mechanism of cytolysis. J Immunol . 1984;;135:25.
31 +
Fiorentino DF, Bond MW, Mosmann TR.  Two types of mouse T helper cell, IV: TH2 clones secrete a factor that inhibits cytokine production by TH1 clones. J Exp Med . 1989;;170:2081.
32 +
Mosmann TR, Moore KW.  The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today . 1991;;12:49.
33 +
Maggi E, Parronchi P, Monetti R, et al.  Reciprocal regulatory effects of IFN-gamma and IL-4 in vitro development of human Th-1 and Th-2 clones. J Immunol . 1992;;148:2142-2147.
34 +
Gajewski TF, Schell SR, Fitch FW.  Evidence implicating utilization of different T cell receptor— associated signalling of pathways by TH1 and TH2 clones. J Immunol . 1990;;144:4110-4120.
35 +
Williams ME, Lichtman AH, Abbas AK.  Anti-CD3 antibody induces unresponsiveness to IL-2 in TH1 clones but not in TH2 clones. J Immunol . 1990;; 144:1208-1214.
36 +
Fathman CG, Myers BD.  Cyclosporin therapy for autoimmune disease. N Engl J Med . 1992;;326: 1693-1695.
37 +
Hricik DE, Almani WY, Strom TB.  Trends in the use of glucocorticoids in renal transplantation. Transplantation . 1994;;57:979-989.
38 +
Miller A, Lider O, Roberts AB, Spron MB, Weiner HL.  Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen specific triggering. Proc Natl Acad Sci U S A . 1992;;89:421-425.
39 +
Weiner HL, Mackin GA, Matsui M, et al.  Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science . 1993;;259:1321-1324.
40 +
Thorbecke GJ, Shab R, Leu CH, Juruvilla AP, Hardison AM, Palladino MA.  Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci USA . 1992;;89:7375-7379.
41 +
Dwyer JM.  Manipulating the immune system with immune globulin. N Engl J Med . 1992;;326: 107-116.

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