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Tippi MacKenzie, MD

Tippi MacKenzie, MD
Associate Professor, Department of Surgery
Research Summary:
Tolerance induction after in utero stem cell transplantation or gene therapy

Fetal surgery was developed at UCSF over 30 years ago as a way of treating select fatal congenital anomalies.  While it has helped hundreds of children with severe anatomic disorders, it is clear that if we could develop safe and effective means of transplanting stem cells into the fetus, we could further transform this field by broadening its scope of diseases.  For example, in utero stem cell transplantation can be used to treat diseases in which stem cells are missing or mutated, such as immunodeficiencies, inborn errors of metabolism, or muscular dystrophy Research in our lab is focused on developing safe and effective stem cell transplantation and other therapies for fetuses with congenital anomalies.

The fetal environment is particularly fertile ground for the success of stem cell transplantation.  We and others have shown that transplanted cells migrate widely in the fetal environment and show enhanced capacity for differentiation.  The main advantage of this strategy is that early in gestation, the fetus is immunologically immature, which gives an opportunity to transplant allogeneic or xenogeneic cells without an immune response. Donor-specific tolerance induction has been achieved in multiple animal models, allowing repeat stem cell or organ transplantation in the postnatal period.  However, clinical applications have been hampered by low engraftment, which has led us to reconsider potential barriers to success.  One conundrum is that while the fetus is widely regarded as immunologically na├»ve, there is evidence that transplanted cells are sometimes rejected.  Our hypothesis is that trafficking of cells between the mother and fetus may influence the immune response to transplantation.  We have recently found that it is the maternal, not fetal immune system that rejects the cells we transplant into the fetus.  We are therefore studying the mechanisms by which this happens as a way to develop strategies to overcome the immune response.  These experiments are performed in a mouse model of fetal stem cell transplantation that is routine in our lab. 

We are also exploring the role of maternal/fetal immune responses as a mechanism of preterm labor in patients undergoing fetal surgery or who have preterm labor from other causes. Preterm birth occurs in about 12% of all pregnancies in the United States and is the leading cause of neonatal morbidity and mortality in the developed world. The effects of premature birth can be devastating throughout the child's life. While inflammation in particular (both as a result of maternal infection and in the context of fetal infection) is widely regarded as being causative for preterm labor, the precise mechanisms leading from inflammation to preterm parturition have not been defined.  We are studying cellular trafficking between the mother and her fetus and its role in the etiology of inflammation-induced preterm labor. We hypothesize that preterm labor may involve alterations in trafficking that could lead to the breakdown of tolerance between the mother and the fetus. We are also exploring the role of maternal T cells in preterm labor in both our mouse model and in patients with preterm labor after fetal surgery.  If we determine that altered trafficking and maternal immune responses are causative in preterm labor, these findings will bring new paradigms for understanding and treating this devastating disease.  We are also studying the pathophysiology of prenatally diagnosed diseases such as congenital diaphragmatic hernia and gastroschisis to identify biomarkers that predict prognosis and molecular pathways that may be targets for prenatal intervention. Thus, research in our lab addresses several important clinical questions by using an array of methods from mouse models to humans. 

Selected Publications

1. Nijagal A, Wegorzewska M, Javis E, Le T, Tang Q, MacKenzie TC. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J Clin Invest. Feb/2011;121(2):582-92. doi: 10.1172/JC144907. Epub 2011 Jan 18.

Reviewed in NEJM Clinical Implications of Basic Research: Parolini O. In utero hematopoietic stem-cell transplantation-a match for mom. N Engl J Med. 2011 Mar 24;364(12):1174-5

2. Nijagal A, Fleck S, Hills NK, Feng S, Tang Q, Kang SM, Rosenthal P, MacKenzie TC. Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia. American Journal of Transpantation. 2012 Feb;12(2):409-19

3. Saadai P, Lee T-H, Bautista G, Gonzales KD, NIjagal A, Busch MP, Kim CJ, Romero R, Lee H, Hirose S, Rand L, Miniati D, Farmer DL, MacKenzie TC. Alterations in maternal-fetal cellular trafficking after fetal surgery. J Pediatr Surg 2012, 2012, Jun;47(6):1089-94.

4. Nijagal A, Flake AW, MacKenzie TC. In utero hematopoietic cell transplantation for treatment of congenital anomalies. Clinics in Perinatology, Jun;39(2):301-10. Epub 2012 May 8.

5. Nijagal A, Wegorzewska M, Javis E, Le T, Tang Q, MacKenzie TC. A mouse model of in utero transplantation. J Vis Exp. 2011 Jan 27;(47). pii: 2303. doi: 10.3791/2303.