History of Pathology & Cell Biology at Columbia

A Treatment for RH Disease

By Eldad Hod, MD, Assistant Professor of Pathology and Cell Biology

Photo of Drs. Eldad Hod and Steven SpitalnikRh disease, a form of hemolytic disease of the fetus and newborn, used to claim the lives of approximately 10,000 babies annually in the United States alone. However, it was virtually eradicated in the 1960's thanks to the efforts of Drs. Vincent Freda and John Gorman at Columbia Presbyterian Hospital. Dr. Freda, an obstetrician, and Dr. Gorman, who completed his residency training in Anatomic and Clinical Pathology at Columbia in 1960 and who was the Blood Bank Director at Columbia, were awarded the Albert Lasker Award for Clinical Medical Research in 1980 for their role in virtually eliminating this devastating disease.

Rh disease results from a blood group incompatibility between the mother and paternally-inherited antigens on fetal red blood cells. Although it can be caused by antigens other than the Rh(D) antigen, this was the most common cause at the time; this would still be true today had it not been for Freda and Gorman's invention of Rhimmune globulin treatment. Historically, an Rh-negative mother (i.e., the mother does not express the Rh(D)-antigen on her red blood cells) becomes immunized to the Rh(D)-antigen during pregnancy when Rh(D)-positive fetal red blood cells cross the placenta into the maternal circulation. During subsequent pregnancies, maternal IgG anti-Rh(D) antibodies can cross the placenta into the fetal circulation and destroy the red blood cells of an Rh(D)-positive fetus. This red blood cell destruction (i.e., hemolysis) can produce hydrops fetalis (i.e., heart failure due to the severe hemolytic anemia). In addition, hemolysis leads to production of bilirubin in the fetus as a by-product of hemoglobin degradation. After delivery, bilirubin is no longer cleared by the placenta and can accumulate in the newborn, which can cause permanent brain damage (i.e., kernicterus).

Although NIH Study Sections failed to fund the project on two separate occasions, commenting that their idea was "nonsense and will never work," Drs. Freda and Gorman persisted in their research. In a landmark study published in Science in 1966, they showed that passive immunization of pregnant women, by injection of exogenous antibodies to Rh(D) (i.e., Rh-immune globulin), within 72 hours of delivery successfully prevented active maternal immunization to Rh(D). This led to the current standard of practice of providing pregnant Rh-negative women with Rh-immune globulin injections twice during pregnancy and also at delivery. This treatment effectively prevents women from making anti-Rh(D) antibodies in virtually every case, thereby preventing Rh disease. The most fascinating aspect of the story scientifically is that we still do not have a complete, mechanistic understanding of how this therapy works. The original hypothesis that Rh-immune globulin functions by clearing fetal Rh(D)-positive red blood cells from the maternal circulation, thereby hiding this foreign antigen from the maternal immune system, is inconsistent with the fact that passive immunization with Rh-immune globulin guides the fetal red blood cells directly to antigen presenting cells, the same cells responsible for initiating an immune response to foreign antigens. Thus, the story is much more complex than initially thought. In addition, perhaps because of this lack of mechanistic understanding, the use of Rh-immune globulin remains the only antigen-specific "immu- Eldad Hod and Steven Spitalnik studiy the stability of red blood cells. Dr. Spitalnik is Vice Chair and the Director of the Clinical Pathology Division. The Institute for Cancer Genetics (ICG) was established in 1999 from a nucleus of cancer researchers in the Department of Pathology. The goal of the ICG was to elucidate the biological processes that cause human cancer, and translate these discoveries into new strategies for improved prevention, diagnosis, and therapy. To achieve these aims, Dr. Riccardo Dalla-Favera, the founding ICG Director, assembled a strong group of investigators who would pursue independent cancer-related research programs while exploiting a shared organizational and cultural framework. With the early support and encouragement of Dr. Shelanski, the initial ICG laboratories were comprised entirely of faculty from the Department of Pathology, including Drs. Benjamin Tycko, Ramon Parsons, Wei Gu, and Richard Baer. The ICG originally occupied space in the Russ-Berrie Pavilion (1999-2005), before moving to the Irving Cancer Research Building in 2005. With the recruitment of key investigators (Antonio Iavarone, Anna Lasorella, Adolfo Ferrando, Jean Gautier, Jose Silva, Shan Zha, and Bin Zheng), the scope of ICG research now encompasses many of the critical areas of human oncology and represents the largest concentration of cancer-related science at Columbia University. One simple measure of this expansion is the level of funding from peer-reviewed grants for research and training, which has increased from ~$1.5 million in 1999 to over $10.0 million in 2012 (annual direct costs). As most of its current faculty still enjoy primary appointments in the Department of Pathology & Cell Biology, the ICG maintains close ties to its origins after thirteen years of growth. By Richard Baer, PhD Those were the days my friend. Riccardo Dalla- Favera studies a sequencing gel, back in the day. nosuppressive" therapy currently approved for use in humans. Investigation into the mechanisms underlying immunization to red blood cell antigens and immune-mediated hemolytic reactions continues in the Department of Pathology & Cell Biology at Columbia University Medical Center; the additional insights gained may allow this type of immunomodulatory therapy to be used in other clinical settings.

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