IVIG & Intralipid Therapy in IVF: Interpreting Natural Killer Cell Activity for Diagnosis and Treatment
IVF and Intralipid Therapy
There is little doubt that there is an ever growing recognition and acceptance of the fact that uterine immunologic dysfunction can lead to “unexplained” infertility, implantation dysfunction, unexplained IVF failure, recurrent pregnancy loss (RPL), and even placental insufficiency. Although there are many autoimmune and alloimmune factors that contribute to such implantation dysfunction, in the final analysis it is the activation of uterine natural killer cells (NKa) (and possibly cytotoxic-T cells) with the release of toxic cytokines that so damage the “root system” (trophoblast) of the embryo that the pregnancy is either immediately rejected, or placentation is compromised, causing pregnancy loss.
There are several methods whereby NKa can be assessed in the laboratory. While methods such as immunohistochemical assessment of uterine NK cells and/or TH-1 and TH-2 cytokines have been used, the gold standard remains the so called K-562 target cell test. In this test, NK cells isolated from the blood through flow Cytometry are incubated with specific target cells and thereupon, NK cell killing is measured. It is important to bear in mind that measurement of NK cell blood concentration has little or no value in assessing NKa.
Currently, probably less than a half dozen Reproductive Immunology Laboratories in the U.S.A are capable of performing the K-562 Target cell test reliably. Both immunoglobulin-G (IVIG) and Intralipid (IL) can successfully down-regulate NKa in the clinical setting.
Presently, virtually all these laboratories compare NK cell activity before and after exposure to IVIG and/or IL. In my opinion, this does not make sense, since neither IVIG nor IL can immediately lower activation of already activated NK cells. The way these therapies achieve such NK cell down-regulation is based upon the way in which they are formed.
This is how it happens, so called “progenitor NK cells” reach the uterus early in the menstrual cycle where, under the effect of estrogen, they undergo proliferation. These “progenitor NK cells” are NOT the ones that influence implantation. This role is effected through their “offspring”, i.e., “functional NK cells” which they propagate after being exposed to progesterone. This is produced after natural or induced ovulation, or following progesterone hormone therapy.
Thereupon it takes approximately 5-7 days for these “progenitors” to spawn a sufficient number of “functional NK cells” at the implantation site to influence orderly implantation. It is by no coincidence that this aligns with the time that the embryo implants into the uterine lining (endometrium).
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells.” For this to happen, the IL/IVIG must influence “progenitor (parent) NK cell” activity. Thus it should be infused several days prior to ovulation or progesterone administration so that the down-regulated “progenitor NK cells” will propagate a sufficient number of normally regulated “functional NK cells” to be present at the implantation site 7 days later.
Even though most Reproductive Immunology Reference Laboratories still report NK cell activity (NKa) before and after IVIG or Intralipid is added to a specimen of activated NK cells, there is in my opinion no value in trying to assess the therapeutic potential of IVIG or IL therapy in this way. Moreover, such information can be misleading. Similarly, there is no real benefit in trying to assess the clinical effect of IL/IVIG immunotherapy by measuring NK cell activity in a woman’s blood sooner than 2 weeks after its administration. Even then, the value of such retesting is probably questionable.
In my opinion, it is very regrettable and unfortunate that so many patients are denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to address the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change …and the sooner the better.