Cytotoxic Lymphocytes (CTLs)
CTLs release “toxins”(perforins and granzymes) and TH-1 cytokines that counter the humoral, TH-2 cytokine response that is a necessary prerequisite for B-cells to produce antibodies. The “toxins” and TH-I cytokines damage or kill the cells that form the outer layers of the embryo’s root system”(i.e.; the trophoblast). By pitting their TH-1 response against the counter-effect of humoral TH-2 cytokines, both CTL’s and activated NK-cells (Nka) regulate and control the degree to which the trophoblast ( placenta) invades the uterine wall as well as the tolerance and acceptance by the uterus of the foreign fetal “transplant” (allographt). Studies have shown that women who experience recurrent pregnancy miscarriages have significantly raised levels of CTL’s, Nka’s and TH-1 Cytokines (the so called “embryotoxic factor”) in their uterine linings as well as in the peripheral blood.
4)Antithyroid Antibodies (ATA)
A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility). We have previously reported on the ability to double IVF birth rates through the administration of IVIg to ATA+ patients. IVIg therapy should be initiated prior to initiation of treatment with fertility drugs, and should be administered one more time after pregnancy is diagnosed. About 50% of women who harbor ATAs also test Nka positive. The risk of implantation failure in ATA positive women appears to be confined to cases where ATAs coexist with Nka. IVIg therapy should be confined to such cases.
THERAPEUTIC IMMUNOMODULATION
1)Corticosteroid Therapy (Prednisone, Prenisolone and Dexamethazone) Steroid therapy is routine in most IVF programs. Some advocates use daily oral methyl prednisolone .We prescribe oral dexamethazone commencing about ten days prior to initiating ovarian stimulation with gonadotropins, and continuing until the diagnosis of pregnancy, whereupon, in the event of a negative test (Beta HCG or ultrasound), the dosage is tapered over a period of seven to ten days, and then discontinued. Pregnant patients continue treatment through the first trimester. Steroids are believed to act by inhibiting the cellular immune response
2)Heparin
There is compelling evidence that the subcutaneous administration of heparin (at a dosage of 5000 U twice daily) to women undergoing IVF for female causes of infertility who test positive for APAs, but negative for NK activation), significantly improves IVF birth rates. Heparin administration is withheld on the day of egg retrieval until immediately following embryo transfer, whereupon it is recommenced and continued until the 8th week of pregnancy. Heparin is thought to act by repelling APAs from the surface of the trophoblast (early "root system" of the embryo). Provided that platelet counts are normal, are checked on a regular basis, and heparin is withheld on the day of egg retrieval, its administration is virtually risk-free.
3)Intravenous Immunoglobulin G (IVIg)
Intravenous Immunoglobulin G (IVIG) is a sterile protein preparation derived from human blood. Every effort has been made to ensure that it is free of bacterial and viral contamination. There are basically four ways in which IVIG is believed to offset or counter the anti-implantation effects associated with reproductive immunologic deficiencies. First, it is a potent suppressor of activated (toxic) Natural Killer cells (NKa). Second, IVIG reduces the activity of CTL’s ( activated T-cells), which are major producers of TH1 cytokines ("toxins") that can damage the early implanting conceptus. Third, IVIG is believed to suppress the ability of B cells to produce damaging autoantibodies such as APAs and antithyroid antibodies (ATA) and, Fourth, IVIG contains anti-idiotype antibodies that directly counter many of the damaging effects of autoantibodies (antibodies that attack the bodies own cells), such as antiphospholipid antibodies (APAs), thereby protecting the early "root system” of the embryo/conceptus from damage.
IVIG has had some undeserved bad press. Since it is a blood derivative, the thought of administering it in an era where HIV is rampant, is frightening to most. However, consider the following: IVIG products available in the United States and the United Kingdom are subject to the most stringent controls and scrutiny. According to the manufacturers of IVIG, there has not been a single case of HIV viral transmission in more than two million administrations and there have only been a few isolated cases of Hepatitis C. This is not surprising since IVIG is derived from the very same blood pool used for transfusion purposes, and since millions of units of blood have been administered in the United States over the last 7 years without any reports of HIV transmission. The IVIG available in the U.S is thoroughly tested .We hold, that if administered properly by qualified medical personnel, and the appropriate precautions are taken, IVIG, currently used in this country, is virtually devoid of viral contamination. We recommend that IVIG for increased NKa be administered at least 7 days prior to embryo/blastocyst transfer.
The selective use of immunotherapy has, on numerous occasions, enabled us to achieve successful pregnancy in patients who had previously suffered repeated IVF failures (4 or more). Many such patients had previously been advised, not to try again with their own eggs. We are able to report IVF births occurring in numerous cases, where the woman had previously experienced more than ten (10) IVF failures. One such case involved a 42-year-old woman who was successful with us (using her own eggs) following 22 consecutive prior IVF failures. We believe that such results could not have been achieved without access to selective immunomodulation.Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:
- Unexplained or recurrent IVF failures
- Endometriosis
- Unexplained infertility or
- A family history of autoimmune diseases (e.g. rheumatoid arthritis, lupus erythematosus & hypothyroidism).
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