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    Advances in Reproductive Immunology
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Recurrent miscarriage and IVF implantation failure affect millions of women annually. It is one of the great failings of the medical community that in as many as 75% of these cases cause is never established. Most often, women are not even tested after miscarrying. What accounts for the rather blasé attitude associated with miscarriage?

Naturally, many factors have conspired to get us where we are today. For one, reproduction is a complex process that requires many different physiological phenomena to happen successfully in the proper order. Second, the human drive to procreate is extremely strong, meaning that couples are unlikely to give up trying to have children even after a miscarriage. And third, nature has a way of appearing to balance out reproductive failings with reproductive successes . . . for instance 60% of women who miscarry go on to bear healthy children at some point. When looked at from this perspective, doctors have chosen to not diagnose and in many cases not treat women for miscarriage. However, from the patients’ perspective, this approach has major shortcomings. Many patients are left frustrated and seemingly without hope.

Fortunately, a new field of study has emerged that will change the way the medical community looks at many reproductive health issues. That field is reproductive immunology. Once relegated to second class stature, significant financial resources and scientific effort have been poured into reproductive immunology over the last 10 years as more and more ties have been drawn between reproductive success and immunologic factors. Nora’s founder, Dr. Darryl Carter, has been at the forefront of many of those efforts as a faculty member at The Johns Hopkins Medical Institution. We think it is past time for many of those recent discoveries to be brought out of the laboratory and into the clinical realm.

The Th1/Th2 Paradigm

Much of the recent research in reproductive immunology has made it eminently clear that a complex transformation has to take place in a woman’s immune system for her to carry a child to term. In particular it appears that her immune system must implement a delicate shift in the balance between two proteins (known as “cytokines” in medical literature) or else she will reject the embryo or fetus as a foreign object. These proteins are classified into two categories, T-helper 1 (Th1) and T-helper 2 (Th2). Th1 and Th2 cytokines are the subject of intense scientific study right now because it is becoming increasingly clear that their interplay underlies the success and failure of the body to assimilate organ transplants, overcome many significant diseases, and to carry a pregnancy to term. In fact, it is not an exaggeration to say that the Th1/Th2 “paradigm” underlies most of the medical efforts to treat major disorders of the immune system today.

Evidence from the most recent scientific studies clearly indicates that an immune response dominated by Th1 cytokines correlates very closely with repeated miscarriage and IVF implantation failure. An immune response dominated by Th2 cytokines correlates very closely with successful pregnancy and IVF implantation.

Nora has taken the research a step further, putting into practice a battery of very sensitive tests that can directly measure levels of Th1 and Th2 cytokines in the blood stream. This unique and complex battery of tests help a woman understand if her immune system is at fault for repeated miscarriage or IVF implantation failure. We do not believe that any other lab in the country can duplicate our capabilities due to subtleties in the measurement process. Furthermore, Nora’s founder, Dr. Darryl Carter, has developed a patent pending treatment that can remedy imbalances in cytokine levels in order to maximize a couple’s chances of carrying a child to term.

Recurrent First Trimester Miscarriage: Inappropriate First Trimester Th1 dominance

In the developed world, our immune systems are predisposed to towards Th1 dominance and away from Th2 dominance. The reason for this has primarily to do with the nature of modern disease. We are much more likely to be affected by viruses than large parasites, for instance, because we have made significant strides in sanitation. Th1 dominance is required to fight viruses while Th2 dominance is required to eliminate large parasites. By and large, our immune systems serve us well. However, in some notable situations like organ transplants, our predisposition towards Th1 dominance lets us down.

You might wonder how organ transplants are relevant to pregnancy and our discussion of miscarriage and IVF implantation failure. It turns out Th1 predominance, in other words an overabundance of Th1 cytokines, is associated not only with organ transplant rejection but also with many cases of first trimester miscarriage and IVF implantation failure. There is a growing understanding that successful pregnancy is dependent upon a rebalancing of the immune system away from Th1 and towards Th2 just as it is in organ transplantation. The mechanism by which a Th1 dominant pattern in the first trimester results in miscarriage or failure of the embryo to implant is also becoming clear.

A fetus, bearing foreign proteins from the father, is partly foreign to the mother, like a transplanted organ. The technical term for the fetus is semi-allogeneic, or “half unrelated.” The initial response of all mothers to partial fetus incompatibility should be a Th1 predominant rejection response; the half unrelated fetus should be rejected in the same way as a totally unrelated transplanted organ. Because of the Th1 rejection response pregnancy should be impossible. What in fact the mother’s body does to make successful pregnancy possible is one of the great miracles of reproduction. Early in the critical first trimester, the mother’s immune system shifts dramatically from its default Th1 dominant state to a period of concerted Th2 dominance. Th2 dominance precludes the possibility that the mother’s immune system will reject the fetus, and children can be carried to term assuming there are no other problems with the pregnancy. However, in some women the shift from Th1 to Th2 dominance fails to happen for unknown reasons. In these cases, the fetus is rejected by the mother’s immune system as a foreign object, much like it might if it were a transplanted organ.

Today, however, we know that organ transplants are routinely successful. This is only the case because major advances have been made in our ability to manipulate the immune system. These scientific advances have lengthened countless lives by enabling organ transplants in cases of liver or kidney disease and by enabling bone marrow transplants in the cases of cancer. However, none of these advances have been applied to reproductive medicine until now. Nora plans to use some of these same methods of immune manipulation to help couples that have suffered through multiple miscarriages or implantation failures to carry children to term.

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