Estrace Day 5
Expounding on LIT
A lazy Sunday. The summer weather here vacillates between nice and "frigging hot". Today it approached the latter and I am a wimp, a complete wimp, when the weather gets hot and/or humid.
I tried to draw J's blood for a LIT treatment but, as he freaks out at the site of needles, a vagal response ensued, his one decent vein disappeared, and it just didn't work. So I'll have a blood nurse come to the house on Saturday and we'll retry again.
It's been one month since my last LIT treatment (aka, paternal alloimmunization) and I'm due for another, especially since the cycle is about to start. I should be starting stims in 3 to 5 days. Stims are notorious for spiking one's natural killer cells, but LIT is a treatment that can put a squelch on that process as well as help the body to create protective blocking antibodies to the paternal HLA-DQ? component of the placenta. The placenta is largely, or entirely (?) formed of tissue that is paternal in origin. In other words, it's totally foreign, whereas the fetus is partially foreign as it's comprised of maternal and paternal genetic material. This junction of paternal/maternal tissue is a potential locus for immunological activity.
IVIg (intravenous immunoglobulins) also works for lowering NK activity, but 20grams of IVIg can run about $1400 plus a $400 to $500 infusion fee. It's not often covered by insurance as they think it's an "off label" use for the product. If you don't have infertility coverage you're double screwed. But back to the nitty gritty of this stuff.
These DQ components can be analyzed. There are DQ-alpha and DQ-beta values that are of importance here. The female and male each have two HLA-DQ-alpha numbers. There is a laboratory in Chicago that can screen for which numbers each partner has, and the percentage of B and T Cells (IgG and IgM) that are present. When the male and female have exactly the same values for this DQ-alpha, the female will find it advantageous to find a donor for LIT. This is just a tiny bit scary as there's a list of diseases to screen for which is an arm's length long. Rh factors also need to be taken into consideration and if the female is Rh- and the husband is Rh+, then the female would of course need a shot of Rhogam. I'm Rh+ and so is J so we don't have an issue here.
So, you think I'm crazy? Yeah, yeah, yeah...read this. There's lots more support available online for this treatment (posting two articles for your reading pleasure):
Am J Reprod Immunol. 2000 Sep ;44 (3):129-35 11028898
Is the paternal mononuclear cells' immunization a successful treatment for recurrent spontaneous abortion?
R Ramhorst , E Agriello , S Zittermann , M Pando , J Larriba , M Irigoyen , M Cortelezzi , L Auge , E Lombardi , J J Etchepareborda , C Contreras Ortiz , L Fainboim
ALLOIMMUNE MPLANTATION DYSFUNCTION:A RATIONAL BASIS FOR SELECTIVE IVIG THERAPY
“The maternal immune system plays a major role in the establishment of a normal Pregnancy. Fetal antigens that are expressed at the maternal-fetal interface, elicit an immune response mechanism which is essential for protecting the fetus from immunologic rejection”
Autoimmunity, i.e where antibodies are produced by an individual, to his/her body’s own antigens, is implicated in >90% of immunologic implantation dysfunction/failure associated with IVF, while infrequently being associated with non-chromosomal RPL.
In contrast alloimmunity, i.e where antibodies (e.g APLA) are formed against antigens (e.g paternal sperm antigens) derived from another member of the same species is believed to be a common cause of non-chromosomal RPL and it is rarely (<10%) associated with IVF failure due to implantation dysfunction.
A pregnancy must be recognized as foreign to trigger the appropriate immunologic mechanisms. Human Leukocyte Antigen (HLA) compatibility plays an important role in this recognition (HLA-A, B, C, DR, DQ and DP). Overall, if the father’s HLA complex too closely resembles the mother’s HLA complex, then this recognition does not occur thus resulting in a spontaneous abortion or implantation failure. HLA-G is a unique HLA that is expressed by cytotrophoblast cells which compose the inner layer of the placenta. The HLA-G isotypes is vital to the maternal tolerance of the fetus and functions as immunosuppressive. In other words, HLA-G serves as a defense mechanism to protect the placenta (embryo) from the maternal NK cells. We recently reported that it is now possible to determine the accurate pregnancy potential of each embryo before IVF implantation. The presence of high levels of sHLA-G had a positive predictive value greater than 70% in women under the age of 39, and over 50% in women from 39 to 44 years old.
Embryonic paternal antigens regulate trophoblastic HLA-G expression which maintains a balanced TH-1: TH-2 release by T-Cell (CD-4) Lymphocytes In the absence of this paternal antigen-induced HLA-G, normal trophoblastic proliferation and embryo implantation cannot occur. When the sperm provider and the embryo recipient share several HLA antigens (e.g HLA, B, C, DR, DQ or DP), there is a break down in HLA-G related cytokine signaling and an imbalance occurs in the TH-1-TH-2 balance with TH-1 cytokines predominating. This often causes progressive or sudden implantation (trophoblastic) failure, most commonly manifesting as recurrent miscarriages and sometimes as unexplained IVF failure.
A positive maternal serum kills freshly drawn paternal peripheral lymphocytes at a proportion >40% of the control-negative serum. Cross match negative couples with either RPL or IVF failure may be candidates for IVIG therapy to suppress natural killer cell activity (Nka)
As stated above, a high rate of HLA loci sharing between the sperm provider (male partner) and the embryo recipient (female partner) is an expression of genetic similarity and may act to prevent implantation. It is the presenting peptides of the relevant HLA loci (A, B, C, DR, DQ) which come in contact with the partner’s T cells (immune cells in the uterine lining) and initiate the immune response cascade. Most couples will share no more than one locus (out of 10 possible alleles inherited from both parents). Several reports, have suggested that genetic similarity, expressed as increased HLA loci sharing, may lead to adverse pregnancy outcome including Recurrent Pregnancy Loss (RPL), low birth weight and pre eclampsia. A number of recent studies have also demonstrated a significant excess of HLA sharing among couples failing multiple induction of ovulation & intrauterine insemination and IVF cycles compared to those who conceive. Two reports support the selective inclusion of DQ alpha/HLA testing in women with unexplained IVF failure and in women with infertility following non-chromosomal RPL. In 1996 one study from the U.S reported on a positive experience with patients treated using IVIg following recurrent IVF failure and a recent study reported out of Israel, evaluated the efficacy of IVIg treatment in patients with >5 recurrent IVF failure all of whom shared several matching HLA Loci with their husbands . More than 40% of the women went on to have babies following intravenous immunoglobulin (IVIG) therapy. Results from my limited experience to date have been similar.
IVIg is a preparation, produced from the plasma of thousands of blood donors that. It has been used for a variety of immunological disorders since 1980. Being a pooled preparation, it has a diverse antibody profile. Several mechanisms have been suggested considering the mode of action of IVIg in modulating the immune system. Some of these proposed mechanisms could theoretically improve implantation and the maintenance of an early pregnancy through enhanced production of T-helper 2 cytokine (TH-2 cytokine producers, inhibition of natural killer cells activity (Nka) and increased antibody production (an anti-idiotypic effect).
We propose treatment with 60G of IVIG 7-10 days prior to ET. This is repeated with the +ve 2nd beta and then given every 5-6 weeks through the 1st , and 2nd trimester and monthly testing of NK cell activity up till 32-34 weeks. Severe side effects of IVIg treatment are rare. Patients may suffer from malaise, fever and headache. In our study one woman suffered from dizziness. IVIg is a relatively expensive mode of treatment - the cost for one course of treatment being 3000-5000 US$ preventing a more wide use of this preparation for experimental indications outside study groups.
We recommend that IVIG in cases for specific clinical conditions where in spite of having transferred numerous “good quality embryos” implantation does not occur and there is associated activation of NK cells when there is a known history or family history of Autoimmune disease in association with the woman testing positive for NK cell activation(Nka+). In cases of Alloimmune implantation failure (see above) Isolated Nk cell activation, without one of these associated clinical situations, is not in and of itself an absolute indication for IVIG therapy since some Nka+ women do conceive and then continue with healthy pregnancies… without IVIG therapy.
It is of great interest to me that with the introduction of the embryo marker expression test (EMET) for the assessment of “embryo competency” prior to embryo transfer (ET) at SIRM we are finding HLA/DQ-alpha sharing of at least 3 alleles in >70% when in spite of having transferred at least one (1) EMET+ embryo a pregnancy did not occur in women <38yrs. Accordingly we recommend DQ alpha and HLA-matching be tested in such cases before proceeding to the next ET.
I tried to draw J's blood for a LIT treatment but, as he freaks out at the site of needles, a vagal response ensued, his one decent vein disappeared, and it just didn't work. So I'll have a blood nurse come to the house on Saturday and we'll retry again.
It's been one month since my last LIT treatment (aka, paternal alloimmunization) and I'm due for another, especially since the cycle is about to start. I should be starting stims in 3 to 5 days. Stims are notorious for spiking one's natural killer cells, but LIT is a treatment that can put a squelch on that process as well as help the body to create protective blocking antibodies to the paternal HLA-DQ? component of the placenta. The placenta is largely, or entirely (?) formed of tissue that is paternal in origin. In other words, it's totally foreign, whereas the fetus is partially foreign as it's comprised of maternal and paternal genetic material. This junction of paternal/maternal tissue is a potential locus for immunological activity.
IVIg (intravenous immunoglobulins) also works for lowering NK activity, but 20grams of IVIg can run about $1400 plus a $400 to $500 infusion fee. It's not often covered by insurance as they think it's an "off label" use for the product. If you don't have infertility coverage you're double screwed. But back to the nitty gritty of this stuff.
These DQ components can be analyzed. There are DQ-alpha and DQ-beta values that are of importance here. The female and male each have two HLA-DQ-alpha numbers. There is a laboratory in Chicago that can screen for which numbers each partner has, and the percentage of B and T Cells (IgG and IgM) that are present. When the male and female have exactly the same values for this DQ-alpha, the female will find it advantageous to find a donor for LIT. This is just a tiny bit scary as there's a list of diseases to screen for which is an arm's length long. Rh factors also need to be taken into consideration and if the female is Rh- and the husband is Rh+, then the female would of course need a shot of Rhogam. I'm Rh+ and so is J so we don't have an issue here.
So, you think I'm crazy? Yeah, yeah, yeah...read this. There's lots more support available online for this treatment (posting two articles for your reading pleasure):
Am J Reprod Immunol. 2000 Sep ;44 (3):129-35 11028898
Is the paternal mononuclear cells' immunization a successful treatment for recurrent spontaneous abortion?
R Ramhorst , E Agriello , S Zittermann , M Pando , J Larriba , M Irigoyen , M Cortelezzi , L Auge , E Lombardi , J J Etchepareborda , C Contreras Ortiz , L Fainboim
PROBLEM: Alloimmunization as a treatment for recurrent spontaneous abortion (RSA) is still controversial due to the lack of enough controls to evaluate its effectiveness. The present study was conducted to compare the live birth rate in the presence or absence of immunotherapy. METHOD OF STUDY: Ninety-two women with RSA (79 primary [PA] and 13 secondary aborters[SA]) received immunotherapy. Thirty-seven RSA couples not receiving paternal alloimmunization, constituted the "control" group. RESULTS: The pregnancy rate in alloimmunized was 58 vs 46% in the control group. The live birth increased from 71% in the controls to 88% after immunotherapy. The alloimmunization induced mixed lymphocyte reaction blocking factors (MLR BFs) in 79% of women. However, they were also present in 83% of immunized women experiencing a new abortion. CONCLUSION: These results indicate that alloimmunization may be useful in the treatment of RSA.
ALLOIMMUNE MPLANTATION DYSFUNCTION:A RATIONAL BASIS FOR SELECTIVE IVIG THERAPY
“The maternal immune system plays a major role in the establishment of a normal Pregnancy. Fetal antigens that are expressed at the maternal-fetal interface, elicit an immune response mechanism which is essential for protecting the fetus from immunologic rejection”
Autoimmunity, i.e where antibodies are produced by an individual, to his/her body’s own antigens, is implicated in >90% of immunologic implantation dysfunction/failure associated with IVF, while infrequently being associated with non-chromosomal RPL.
In contrast alloimmunity, i.e where antibodies (e.g APLA) are formed against antigens (e.g paternal sperm antigens) derived from another member of the same species is believed to be a common cause of non-chromosomal RPL and it is rarely (<10%) associated with IVF failure due to implantation dysfunction.
A pregnancy must be recognized as foreign to trigger the appropriate immunologic mechanisms. Human Leukocyte Antigen (HLA) compatibility plays an important role in this recognition (HLA-A, B, C, DR, DQ and DP). Overall, if the father’s HLA complex too closely resembles the mother’s HLA complex, then this recognition does not occur thus resulting in a spontaneous abortion or implantation failure. HLA-G is a unique HLA that is expressed by cytotrophoblast cells which compose the inner layer of the placenta. The HLA-G isotypes is vital to the maternal tolerance of the fetus and functions as immunosuppressive. In other words, HLA-G serves as a defense mechanism to protect the placenta (embryo) from the maternal NK cells. We recently reported that it is now possible to determine the accurate pregnancy potential of each embryo before IVF implantation. The presence of high levels of sHLA-G had a positive predictive value greater than 70% in women under the age of 39, and over 50% in women from 39 to 44 years old.
Embryonic paternal antigens regulate trophoblastic HLA-G expression which maintains a balanced TH-1: TH-2 release by T-Cell (CD-4) Lymphocytes In the absence of this paternal antigen-induced HLA-G, normal trophoblastic proliferation and embryo implantation cannot occur. When the sperm provider and the embryo recipient share several HLA antigens (e.g HLA, B, C, DR, DQ or DP), there is a break down in HLA-G related cytokine signaling and an imbalance occurs in the TH-1-TH-2 balance with TH-1 cytokines predominating. This often causes progressive or sudden implantation (trophoblastic) failure, most commonly manifesting as recurrent miscarriages and sometimes as unexplained IVF failure.
A positive maternal serum kills freshly drawn paternal peripheral lymphocytes at a proportion >40% of the control-negative serum. Cross match negative couples with either RPL or IVF failure may be candidates for IVIG therapy to suppress natural killer cell activity (Nka)
As stated above, a high rate of HLA loci sharing between the sperm provider (male partner) and the embryo recipient (female partner) is an expression of genetic similarity and may act to prevent implantation. It is the presenting peptides of the relevant HLA loci (A, B, C, DR, DQ) which come in contact with the partner’s T cells (immune cells in the uterine lining) and initiate the immune response cascade. Most couples will share no more than one locus (out of 10 possible alleles inherited from both parents). Several reports, have suggested that genetic similarity, expressed as increased HLA loci sharing, may lead to adverse pregnancy outcome including Recurrent Pregnancy Loss (RPL), low birth weight and pre eclampsia. A number of recent studies have also demonstrated a significant excess of HLA sharing among couples failing multiple induction of ovulation & intrauterine insemination and IVF cycles compared to those who conceive. Two reports support the selective inclusion of DQ alpha/HLA testing in women with unexplained IVF failure and in women with infertility following non-chromosomal RPL. In 1996 one study from the U.S reported on a positive experience with patients treated using IVIg following recurrent IVF failure and a recent study reported out of Israel, evaluated the efficacy of IVIg treatment in patients with >5 recurrent IVF failure all of whom shared several matching HLA Loci with their husbands . More than 40% of the women went on to have babies following intravenous immunoglobulin (IVIG) therapy. Results from my limited experience to date have been similar.
IVIg is a preparation, produced from the plasma of thousands of blood donors that. It has been used for a variety of immunological disorders since 1980. Being a pooled preparation, it has a diverse antibody profile. Several mechanisms have been suggested considering the mode of action of IVIg in modulating the immune system. Some of these proposed mechanisms could theoretically improve implantation and the maintenance of an early pregnancy through enhanced production of T-helper 2 cytokine (TH-2 cytokine producers, inhibition of natural killer cells activity (Nka) and increased antibody production (an anti-idiotypic effect).
We propose treatment with 60G of IVIG 7-10 days prior to ET. This is repeated with the +ve 2nd beta and then given every 5-6 weeks through the 1st , and 2nd trimester and monthly testing of NK cell activity up till 32-34 weeks. Severe side effects of IVIg treatment are rare. Patients may suffer from malaise, fever and headache. In our study one woman suffered from dizziness. IVIg is a relatively expensive mode of treatment - the cost for one course of treatment being 3000-5000 US$ preventing a more wide use of this preparation for experimental indications outside study groups.
We recommend that IVIG in cases for specific clinical conditions where in spite of having transferred numerous “good quality embryos” implantation does not occur and there is associated activation of NK cells when there is a known history or family history of Autoimmune disease in association with the woman testing positive for NK cell activation(Nka+). In cases of Alloimmune implantation failure (see above) Isolated Nk cell activation, without one of these associated clinical situations, is not in and of itself an absolute indication for IVIG therapy since some Nka+ women do conceive and then continue with healthy pregnancies… without IVIG therapy.
It is of great interest to me that with the introduction of the embryo marker expression test (EMET) for the assessment of “embryo competency” prior to embryo transfer (ET) at SIRM we are finding HLA/DQ-alpha sharing of at least 3 alleles in >70% when in spite of having transferred at least one (1) EMET+ embryo a pregnancy did not occur in women <38yrs. Accordingly we recommend DQ alpha and HLA-matching be tested in such cases before proceeding to the next ET.
Labels: IVF3 Take 3
posted by linda at 1:29 AM
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Expounding on LIT"
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