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Role of Immunotherapy in ART

Role of Immunotherapy in ART. 한림의대 산부인과 서 수 형. Introduction. 1993, ASRM Implantation rate per ET: 10 – 15% enhanced protocols for COH improved embryo culture techniques assisted hatching ICSI

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Role of Immunotherapy in ART

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  1. Role of Immunotherapy in ART 한림의대 산부인과 서 수 형 HLMC

  2. Introduction 1993, ASRM • Implantation rate per ET: 10 – 15% enhanced protocols for COH improved embryo culture techniques assisted hatching ICSI • morphologically normal embryo, not much above 20% per egg retrieval HLMC

  3. Historical review 1978 Steptoe and Edwardthe first test tube baby was born 1986 Navot et alovum donation model – window of embryo transfer 1986 Clark et al : 1987 Allen et aldevelopment of animal model for implantation 1987 Gleicher et alincreased prevalence of antiphospholipid antibody in patient with pelvic endometriosis HLMC

  4. Historical review 1989 Navot et aluterine receptivity and embryonic-uterine interaction 1991 Fisch et alautoantibodies to phospholipid in unsuccessful IVF-ET cycles 1992 Dwyerclinical use of intravenous immunoglobulin for inflammatory response 1994 De Placido et alintravenous Ig use for IVF/ET HLMC

  5. Historical review 1994 Sher et aluse of low dose heparin and aspirin in IVF failure patients 1997 Bustilo et aluse of GM-CSF in IVF failure patients 1998 Sher et alcombination immunotherapy in IVF patient with antiphospholipid antibody 1999 Würfel et aluse of GM-CSF and G-CSF in recurrent IVF failure group HLMC

  6. Complex immune mechanisms on implantation local uterine and systemic immune response • decreased in cell-mediated immunity and increased in humoral immunity • mediated by inhibitory subset of T-helper (TH cell) • increased concentrations of PGE2 and PGF2α at the implantation site • increase vascular permeability HLMC

  7. Autoimmune disorders • estrogen regulate the synthesis of Ig and production of autoantigens • estrogens interacts with specific steroid receptors in CD 8+ T cells and in CD 5+ B cells • premature ovarian failure, autoimmune endocrine disease • autoimmune disorders; high incidence of pregnancy wastage -SLE, scleroderma, Hashimoto’s thyroiditis HLMC

  8. Cellular surface phospholipid • functions; adhesion molecule in the formation of myoblast and syncytiotrophoblast • local or systemic tissue damage; pelvic inflammatory disease, endometriosis, post-surgical adhesions • converts from a bilaminar configuration to a hexagonal phase II structure • combine with lipoprotein; antigenic HLMC

  9. Platelet activation factor (PAF) • ether-linked phospholipid • produced by blastocyst, invading trophoblast, adjacent decidua • facilitates implantation; increasing local consumption of thrombocytes • promoting release of PGE2 • promotes local production of early pregnancy factor, an immunosuppressive glycoprotein HLMC

  10. Antiphospholipid antibody (APA) • main antibody from non-specific tissue injury • response to variety of phospholipids, extra- and intracellularly • APA seropositive; 5 to 17% in general populationvs 59% in recurrent spontaneous abortion (RSA) group • phospholipid epitopes; phosphoethanolamine, phosphoserin, phosphatidic acid, phosphoinositol, phosphoglycerol, cardiolipin HLMC

  11. APA and pregnancy wastage • transient production during ovarian stimulation and /or as a consequence of oocyte retrieval disappearance within several weeks • bind with surface phospholipid on the trophoblast; direct cellular injury and inhibition of syncytia formation • platelet membrane and/or endothelial cell wall damage; indirect damage through intravascular thrombosis • inhibition of prostacyclin and inability to activate protein C; hypercoagulable state • interfere with the adhesive property of phospholipid in the process of implantation HLMC

  12. Anticardiolipin antibody (ACA) • the earliest of the APAs to be identified • cardiolipin endomitochodrially bound and deep seated within the cell • less antigenic and less likely form APAs • less frequently detected than other APAs • the least threat to the trophoblast • 6% positive in study groupvs0 to 3 % in control group HLMC

  13. Lupus anticoagulant (LAC) • conglomerate of a wide variety of non-cardiolipin APAs • diagnosing primary autoimmune states relatively high concentrations of APA • lack of sufficient sensitivity and specificity to diagnose low concentrations of APA • highly unreliable in assessing autoimmunity in association with reproductive failure and infertility HLMC

  14. Antithyroid antibody (TA) • prevalence of underlying subtle thyroid abnormality; 17% • increased risk of spontaneous abortion 13.3% vs 3.3% in control (p<.001) • high incidence of reproductive failure, recurrent miscarriages, and IVF failure HLMC

  15. Human histocompatibility antigen HLA-G • HLA-G expression in early cytotrophoblast • shield the fetus from rejection • eliciting local production of maternal suppressor cells • protective blocking antibody • being nonrecognizable HLMC

  16. Peripheral blood lymphocytes • CD56+/CD16- T-lymphocyte NK (natural killer) cell • elevated NK cell; presence of antiphospholipid antibody (APA) • elevated CD19+/CD5+ B lymphocyte; antibodies to DNA and DNA components • measuring NK cell; far easier than quantitating APA levels • predictors of reproductive failure in RSA and infertility with prior IVF failure HLMC

  17. Immunotherapy • heparin • aspirin • intravenous Ig • corticosteroids • GM-CSF/G-CSF HLMC

  18. Heparin • endogenous production by trophoblast • inhibits biding of APA with trophoblast • prevents APA from interfering with syncytialization • counters APA interference with phospholipid-induced decidual reactions • promotes both early implantation and subsequent placentation HLMC

  19. Aspirin • anti-thromboxane effects • inhibits platelet aggregation • counter APA-mediated hypercoagulability in the choriodecidual space • hemo-chorial relationship; established with placentation • protect the trophoblast from damage after establishment of placentation HLMC

  20. Intravenous immunoglobulin • passively transferred blocking or anti-idiotypic antibodies • blockade of Fc receptors • enhancing suppressor T cell function • down-regulation of B cell function • reduction of activation of complement components • reduction of activation of NK cells to activated killer (LAK) cells HLMC

  21. Intravenous immunoglobulin • i.v. Ig 500 mg/kg prior to embryo transfer • repetitive i.v. Ig 500 mg/kg every 28 days until delivery or until 28-32 weeks of gestation HLMC

  22. Corticosteroids • controversial and questionable • 60 mg of methylprednisolone for 4 days • diminish the uterine T-lymphocytes • suppressing T-cell function; decreased implantation rate and increased abortion rate HLMC

  23. GM-CSF • product of activated T-lymphocyte • proliferation and differentiation of myeloid hematopoietic cells • produced by estrogen-primed epithelial cell in the oviduct and uterus • antibodies to T-suppressor (CD 8+) cells; increased abortion rate in mice • monoclonal anti GM-CSF; increases abortion rate in mice • anti CD 8+ treatment; block the protective effect of GM-CSF HLMC

  24. Incidence of Autoimmune Antibodies in Failed Embryo Transfer CycleBirkenfeld et al; AJRI 1994, Mount Sinai Sch of Med • Group I 56 patients who are failed to conceive following ET 18 (32.1%), positive for one or more Abs • Group II 14 patients who have conceived following IVF-ET none of the patients positive for Ab’s (p<.02) • Group III 69 patients who were new candidates for IVF-ET 7 (10%), positive for autoimmune Ab’s (p<.003) HLMC

  25. Incidence of Autoimmune Antibodies in Failed Embryo Transfer CycleBirkenfeld et al; AJRI 1994, Mount Sinai Sch of Med • 15 of the 18 positive patients subsequent IVF-ET cycle • 10 mg of prednisolone + 80 mg of aspirin daily • beginning 2 weeks prior to the initiation of the cycle • 7 (46.6%), conceived and ongoing pregnancy HLMC

  26. Antiphospholipid Antibody Treated with Heparin and AspirinG Sher and M Feinman Hum Reprod 1994, Pacific Fertility Med Cntr • the first IVF-ET cycle • ELISA for six different phospholipids • aspirin 81 mg orally q.d., and heparin 5000 IU s.c. b.i.d. • beginning on day 2 of COH through the 34weeks of pregnancy HLMC

  27. Antiphospholipid Antibody Treated with Heparin and AspirinG Sher and M Feinman Hum Reprod 1994, Pacific Fertility Med Cntr • prevalence of APA 53% in patients with organic pelvic diseasevs14% without pathology • viable pregnancy rate in APA seropositive pts 49% in H/A group vs16% in untreated group (p<.05) vs27% in untreated seronegative group (p<.001) HLMC

  28. Combined heparin/aspirin and Ig G therapy in IVF with APA G Sher et al; AJRI 1998, Pacific Fertility Med Cntr • 89 women <36 years of age, experienced 4 or more failed IVF/ET cycle • group A; 52 women – APA positive • group B; 37 women – APA negative • live birth rate; A : B = 42% : 19% (p=.020) HLMC

  29. Combined heparin/aspirin and Ig G therapy in antithyroid antibodyG Sher et al; AJRI 1998, Pacific Fertility Med Cntr • 82 women <40 years of age with ATA but negative for APA • group A; 37 women - received H/A alone • group B; 45 women - received H/A with IVIg • live birth rate after single IVF/ET cycle A : B = 27% : 51% (p=.027) HLMC

  30. Effect of APA in IVF : role of heparin and aspirinW Kutteh et al; Hum Reprod 1997, Memphis Positive APA 18.8% of 191 patients in IVF group vs5.5% of 200 normal control group 26% of APA+ in 200 women with recurrent pregnancy loss heparin and aspirin treatment no statistical differences in implantation and pregnancy rate HLMC

  31. Birdsall in Oxford, Hum Reprod 1996; APA • 240 women <38years, fewer than three previous IVF cycles • APA, not associated with a failed IVF cycle or miscarriage • no association between the cause of infertility and the presence of APA A Kowalik in Cornell, Fertil Steril 1997; • ACA and antiphosphatidylserine antibody • no correlation between outcome and the antibody isotype expressed HLMC

  32. A Denis and R Scott; Fertil Steril 1997, Pennsylvania elevated APA levels, not associated with any change in PRs or pregnancy loss rates F Azem et al; AJRI 1998, Tel Aviv anticardiolipin antibody (ACA) with abnormal embryo morphology HLMC

  33. S Spandorfer and Z Rosenwaks; AJRI 1998, Cornell Univ. GM-CSF by endometrial co-culture in IVF with multiple implantation failure C Sjoblom et al; Hum Reprod 1999, Sweden GM-CSF promotes blastocyst development HLMC

  34. In-vitro processing of sperm with autoantibodiesM Almeida et al; Hum Reprod 1989, France 20 infertile couples with anti-sperm antibodies overall fertilization rate 38.9% in post-migration (PM) 14% in antibody-coating >70% group vs60% in <70% post-migration immuno-depleted sperm preparation (PMP) with Mage’s plate 10 couples with PMP; containing <65% of antibody-coated spermatozoa,31% fertilized fertilization rate;10% in PM vs 26% in PMP HLMC

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