Electron microscopic image of a human lymphocyte. Image source: Public domain image via Wikimedia Commons
The term “lymphocyte immunization” is rarely heard since 2002, when the _Food and Drug Administration (FDA) _prohibited this treatment in the U.S. outside of clinical trials. Up to that point, immunomodulation of the maternal immune response to paternal antigens on the trophoblast via active immunization with partner-lymphocytes was common practice.
The hypothesis behind this treatment was that stimulation of a hypo-reactive maternal immune system by paternal antigens on lymphocytes will, in a subsequent pregnancy, lead to improved immune-recognition of the implanting embryo and, therefore, in the maternal immune system to better induction of what now is recognized as tolerance pathways. The expectation was that such treatment would improve implantation and reduce the risk of miscarriages.
Because of the _FDA _edict, lymphocyte immunization is since 2002 no longer available as clinical treatment in the U.S.A. However, a considerable number of U.S. patients still travel to receive such treatments, with Mexico being the primary destination. Lymphocyte immunizations are, however, also available in many other countries, including in Europe. A first serious formal claim for the treatment’s efficacy was, indeed, made by British investigators.
The treatment was originally primarily only given to patients with repeated pregnancy losses. When first proposed, these treatments were only reserved for women with confirmed hypo-reactivity toward the male partners’ antigens, usually diagnosed in vitro with specific lymphocyte mixing tests. Over time, criteria for utilization were expanded and lymphocyte immunization became almost a standard treatment for all patients with repeat pregnancy loss and, increasingly, was also considered treatment for the so-called implantation failure. The latter is, of course, a rather problematic diagnosis because nobody knows how to define implantation failure and, therefore, how to reach such a diagnosis in reproducible fashion. No wonder reported outcomes after lymphocyte immunizations were all over the scale and the procedure remained highly controversial.
CHR never utilized lymphocyte immunization as a treatment for either repeated pregnancy loss or implantation failure. Even before the FDA’s edict, CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, urged caution in using paternal lymphocyte immunization for fear of inducing autoimmune reactions in mothers. He proved prescient in that concern. Even among the treatment’s proponents, evidence of autoimmunity is currently considered an absolute contraindication for the treatment. The problem with this approach, as Gleicher pointed out 30 years ago, lies in the fact that so many women with infertility and/or repeated pregnancy loss suffer from subclinical autoimmunity, which will be detected only through appropriate investigations (and even then, not always). To simply rely on a history of autoimmunity does not appear adequate.
Induction of autoimmunity will, of course, have exactly the opposite effects on miscarriage risk as one expects from lymphocyte immunization. Frequently discussed in these pages before, autoimmunity is an almost certain way to create a hyper-active immune system, which does not appropriately induce required tolerance pathways for the products of conception by the maternal immune system. In such cases, lymphocyte immunization can, therefore, actually further increase miscarriage risks. Unsurprisingly, CHR has remained skeptical of the concept and still does not recommend lymphocyte immunization as a treatment.
This is a part of the September 2019 CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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