Pathogens and foreign material are recognized by the immune system and can be rapidly cleared via innate/humoral and adaptive mechanisms. Yet during pregnancy, the embryo/fetus is protected and nurtured despite the expression of foreign paternal antigens. It is suggested that a state of tolerance without immune suppression is achieved between the mother and fetus/embryo, preventing both rejection and graft-versus-host-disease(GvHD).
Post fertilization, the embryo becomes surrounded by the zona pellucida which effectively creates an environment where substances can be excreted but the maternal immune system cannot access the expressed foreign paternal antigens. Tolerance of the embryo is not specific to the uterine cavity since implantation may occur in the fallopian tube, ovary or, rarely, the abdominal cavity. Even allogenic (as in donor ovum) embryos routinely survive to term in In-Vitro Fertilization procedures despite containing entirely foreign antigens.
The recent literature indicates that pregnancy does not generate immune-suppression but rather a state of controlled inflammation. During implantation, the endometrium is remodeled to allow blood vessel penetration. The remodeling can be so aggressive that maternal immune response (Th-1) is needed to prevent over-invasion. However, if the immune response shifts to Th-2, over-suppression occurs resulting in decreased angiogenesis and embryo rejection.
This shift is an important mechanism for the expulsion of defective or seriously infected embryos. It is estimated that more than 95% of defective embryos are terminated early due to the lack of proper immune tolerance. Barnea shows that an embryo-derived protein, preimplantation factor (PIF), has a role in initiation of maternal tolerance and receptivity of the uterus to implantation. This is the first time that a clearly embryo-derived factor has been found in early pregnancy (in the embryo/fetus and placenta) and also in maternal peripheral circulation. Presence of PIF in maternal blood within 4 days of embryo transfer, increased the delivery rate to more than 70% to term versus the 3% delivery rate if implantation was delayed.
It has been shown that symptoms of some autoimmune disorders improve during pregnancy. Women with Multiple Sclerosis (MS) show major symptom improvement in the third trimester but experience rapid flare-up after delivery. Insulin requirements for women with juvenile diabetes mellitus (JDM) decrease 12% during early pregnancy but then increase to 50%. Interestingly, PIF also has the ability to modulate the immune response in autoimmune disorders and prevents the development of GvHD in semiallogenic animal transplants.
In the mouse autoimmune encephalitis (EAE) model for MS, low-dose short-term PIF administration on non-pregnant mice reduced paralysis, delayed initiation of the disease and increased the survival of the animals. IL-12 is a major inflammatory cytokine implicated in MS, and PIF also decreased the IL-12 serum level. PIF’s mechanism in JDM acts to protect insulin producing Langerhans cells from destruction. PIF therapy also prevented skin ulceration, hepatitis and severe weight loss in a GvHD model that transferred semiallogenic immune cells to irradiated mice.
This 15-amino acid peptide appears to modulate immune tolerance in organ systems as varied as spinal cord, pancreas, skin, liver and bone marrow. It was shown to be non-toxic, even at very high doses in vivo, and can be easily synthesized. Which suggests it could be a prime candidate for drug development in the treatment of autoimmune disorders. The research in this area is ongoing (manuscripts in preparation) and may transition from preclinical to clinical trials in the near future.
Barnea, E.R. Applying Embryo-Derived Immune Tolerance to the Treatment of Immune Disorders. Ann.N.Y.Acad.Sci. 1110: 602-618(2007).
4 comments:
Wow -- very interesting that immune tolerance is increased during pregnancy in women and in mouse models with an injection of PIF. Have you read anything about the effect of PIF on men since the substance is not usually present in male circulation?
Since the mouse model EAE for MS was short term i wonder if there would be any negative side effects to the body if PIF is administerd on a long term basis, so it would be great to see studies in the near future that address this issue. I thought your blog was interesting and it also made me wonder if PIF is a contributing factor as to why pregant women rarely get sick.
The idea that pregnancy is not an immuno-suppressed state is interesting and new to me. I wonder how widely this idea is accepted or communicated. Having recently been pregnant myself, it seemed to be a known fact among the medical community that pregnancy was immuno-suppresive. A recent study of mice supported this theory in regard to TLR expression.
Reference: Gonzalez JM, et al. Am J Obstet Gynecol 2007;197(3):296.e1-6.
Jessica, I haven't found any studies looking at PIF administration in men. Even the published animal experiments focus on pregnant mice or female mice with induced autoimmunity. I also could not find out if PIF composition and structure varied if the mice/women carried a female or male fetus.
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