TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm

Abstract

In this paper, we briefly survey the history of concepts in reproductive immunology from antibody-mediated tolerance to the "fetal allograft" to the current concept of an embryo "bathing in a sea of cytokines". We then review the paradigm that "allopregnancy is a Th2 phenomenon" and some of the evidence gained in animals and humans supporting it. We continue by discussing the light it sheds on immunologically caused recurrent abortion, and the present status of the concepts. We next show the limits of the Th1/Th2 paradigm by reviewing the role of "inflammatory" cytokines in implantation (as first seen with leukemia inhibitory factor). We go on to discuss recent data showing that interferon-gamma is not solely a "bad guy", e.g. abortifacient as the paradigm would predict, but is needed at low doses for the vascular development and transformation of uterine spiral arteries required for implantation and successful pregnancy. We conclude by discussing the emerging role of NK and IL-12, IL-15, IL-18 tripods and other cytokines in local angiogenesis and tissue remodelling, a series of new data bringing us well beyond the Th1/Th2 paradigm in pregnancy which, in this context, appears now obsolete and an oversimplification, although it has indeed been useful at first. Rather, step-specific events have to be considered and a key role is seen in local tissue remodelling, in which immune cytokines play an important role while not always being secreted by immune cells.