Tippi Mackenzie, MD

Associate Professor
Department of Surgery

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 naïve, 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.

Research Summary: 
Tolerance induction after in utero stem cell transplantation or gene therapy

Websites

Publications: 

CD161 contributes to prenatal immune suppression of IFN?-producing PLZF+ T cells.

The Journal of clinical investigation

Halkias J, Rackaityte E, Hillman SL, Aran D, Mendoza VF, Marshall LR, MacKenzie TC, Burt TD

In Utero Gene Therapy Consensus Statement from the IFeTIS.

Molecular therapy : the journal of the American Society of Gene Therapy

Almeida-Porada G, Waddington SN, Chan JKY, Peranteau WH, MacKenzie T, Porada CD

Evaluation of Clinical Outcomes of Sutureless vs Sutured Closure Techniques in Gastroschisis Repair.

JAMA surgery

Witt RG, Zobel M, Padilla B, Lee H, MacKenzie TC, Vu L

Large Differences in Small RNA Composition Between Human Biofluids.

Cell reports

Godoy PM, Bhakta NR, Barczak AJ, Cakmak H, Fisher S, MacKenzie TC, Patel T, Price RW, Smith JF, Woodruff PG, Erle DJ

Future AAVenues for In Utero Gene Therapy.

Cell stem cell

MacKenzie TC

Meta-Analysis of Maternal and Fetal Transcriptomic Data Elucidates the Role of Adaptive and Innate Immunity in Preterm Birth.

Frontiers in immunology

Vora B, Wang A, Kosti I, Huang H, Paranjpe I, Woodruff TJ, MacKenzie T, Sirota M

Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-? and TNF-a.

Science translational medicine

Frascoli M, Coniglio L, Witt R, Jeanty C, Fleck-Derderian S, Myers DE, Lee TH, Keating S, Busch MP, Norris PJ, Tang Q, Cruz G, Barcellos LF, Gomez-Lopez N, Romero R, MacKenzie TC

Systemic multilineage engraftment in mice after in utero transplantation with human hematopoietic stem cells.

Blood advances

Witt RG, Kreger EM, Buckman LB, Moradi PW, Ho PT, Derderian SC, Tsai P, Baker C, Schramm N, Cleary R, Garcia JV, MacKenzie TC

Esophagoesophagopexy technique for assisted fistulization of esophageal atresia.

Pediatric surgery international

Chumfong I, Lee H, Padilla BE, MacKenzie TC, Vu LT

Non-Immune Hydrops Fetalis: Do Placentomegaly and Polyhydramnios Matter?

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine

Berger VK, Sparks TN, Jelin AC, Derderian C, Jeanty C, Gosnell K, Mackenzie T, Gonzalez JM

Sacrococcygeal teratoma: late recurrence warrants long-term surveillance.

Pediatric surgery international

Padilla BE, Vu L, Lee H, MacKenzie T, Bratton B, O'Day M, Derderian S

Fetal stem cell and gene therapy.

Seminars in fetal & neonatal medicine

Witt R, MacKenzie TC, Peranteau WH

Epidemiology of Live Born Infants with Nonimmune Hydrops Fetalis-Insights from a Population-Based Dataset.

The Journal of pediatrics

Steurer MA, Peyvandi S, Baer RJ, MacKenzie T, Li BC, Norton ME, Jelliffe-Pawlowski LL, Moon-Grady AJ

Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature.

Prenatal diagnosis

Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E

A Transient Developmental Hematopoietic Stem Cell Gives Rise to Innate-like B and T Cells.

Cell stem cell

Beaudin AE, Boyer SW, Perez-Cunningham J, Hernandez GE, Derderian SC, Jujjavarapu C, Aaserude E, MacKenzie T, Forsberg EC

Magnetic resonance imaging of Müllerian duct anomalies in children.

Pediatric radiology

Li Y, Phelps A, Zapala MA, MacKenzie JD, MacKenzie TC, Courtier J

Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.

Journal of immunology (Baltimore, Md. : 1950)

Frascoli M, Jeanty C, Fleck S, Moradi PW, Keating S, Mattis AN, Tang Q, MacKenzie TC

Mass Effect Alone May Not Explain Pulmonary Vascular Pathology in Severe Congenital Diaphragmatic Hernia.

Fetal diagnosis and therapy

Derderian SC, Jayme CM, Cheng LS, Keller RL, Moon-Grady AJ, MacKenzie TC

A booster shot to cure hemoglobinopathies.

Blood

Walters MC, MacKenzie TC

Maternal factors associated with the occurrence of gastroschisis.

American journal of medical genetics. Part A

Baer RJ, Chambers CD, Jones KL, Shew SB, MacKenzie TC, Shaw GM, Jelliffe-Pawlowski LL

Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy.

Frontiers in pharmacology

MacKenzie TC, David AL, Flake AW, Almeida-Porada G

In utero hematopoietic cell transplantation for hemoglobinopathies.

Frontiers in pharmacology

Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC

Placental drug delivery for treatment of congenital hematopoietic disorders.

Journal of pediatric surgery

Derderian SC, Moradi PW, MacKenzie TC

The many faces of hydrops.

Journal of pediatric surgery

Derderian SC, Jeanty C, Fleck SR, Cheng LS, Peyvandi S, Moon-Grady AJ, Farrell J, Hirose S, Gonzalez J, Keller RL, MacKenzie TC

Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia.

Seminars in fetal & neonatal medicine

Jeanty C, Kunisaki SM, MacKenzie TC

Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone.

Journal of pediatric surgery

Derderian SC, Coleman AM, Jeanty C, Lim FY, Shaaban AM, Farrell JA, Hirose S, MacKenzie TC, Lee H

Maternal-fetal cellular trafficking: clinical implications and consequences.

Current opinion in pediatrics

Jeanty C, Derderian SC, Mackenzie TC

In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.

Blood

Derderian SC, Togarrati PP, King C, Moradi PW, Reynaud D, Czechowicz A, Weissman IL, MacKenzie TC

Memory regulatory T cells reside in human skin.

The Journal of clinical investigation

Sanchez Rodriguez R, Pauli ML, Neuhaus IM, Yu SS, Arron ST, Harris HW, Yang SH, Anthony BA, Sverdrup FM, Krow-Lucal E, MacKenzie TC, Johnson DS, Meyer EH, Löhr A, Hsu A, Koo J, Liao W, Gupta R, Debbaneh MG, Butler D, Huynh M, Levin EC, Leon A, Hoffman WY, McGrath MH, Alvarado MD, Ludwig CH, Truong HA, Maurano MM, Gratz IK, Abbas AK, Rosenblum MD

Outcomes of fetal intervention for primary hydrothorax.

Journal of pediatric surgery

Derderian SC, Trivedi S, Farrell J, Keller RL, Rand L, Goldstein R, Feldstein VA, Hirose S, MacKenzie TC

Fetal intervention increases maternal T cell awareness of the foreign conceptus and can lead to immune-mediated fetal demise.

Journal of immunology (Baltimore, Md. : 1950)

Wegorzewska M, Nijagal A, Wong CM, Le T, Lescano N, Tang Q, MacKenzie TC

Anal duplication in a one-year-old girl.

Journal of pediatric surgery case reports

Cheng LS, Courtier J, MacKenzie TC

Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia.

Pediatric research

Fleck S, Bautista G, Keating SM, Lee TH, Keller RL, Moon-Grady AJ, Gonzales K, Norris PJ, Busch MP, Kim CJ, Romero R, Lee H, Miniati D, MacKenzie TC

Clinical implications of maternal-fetal cellular trafficking.

Seminars in pediatric surgery

Nijagal A, MacKenzie TC

Hepatic portocholecystostomy for biliary atresia: a 25-year follow-up and review.

Journal of pediatric surgery

Schecter SC, Courtier J, Cho SJ, Saadai P, Hirose S, Mackenzie TC, Miniati D

The diagnosis and management of intradiaphragmatic extralobar pulmonary sequestrations: a report of 4 cases.

Journal of pediatric surgery

Nijagal A, Jelin E, Feldstein VA, Courtier J, Urisman A, Jones KD, Lee H, Hirose S, MacKenzie TC

Alterations in maternal-fetal cellular trafficking after fetal surgery.

Journal of pediatric surgery

Saadai P, Lee TH, Bautista G, Gonzales KD, Nijagal A, Busch MP, Kim CJ, Romero R, Lee H, Hirose S, Rand L, Miniati D, Farmer DL, MacKenzie TC

Long-term outcomes after fetal therapy for congenital high airway obstructive syndrome.

Journal of pediatric surgery

Saadai P, Jelin EB, Nijagal A, Schecter SC, Hirose S, MacKenzie TC, Rand L, Goldstein R, Farrell J, Harrison M, Lee H

In utero hematopoietic cell transplantation for the treatment of congenital anomalies.

Clinics in perinatology

Nijagal A, Flake AW, MacKenzie TC

Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

Nijagal A, Fleck S, Hills NK, Feng S, Tang Q, Kang SM, Rosenthal P, MacKenzie TC

Pancreatic mesenchyme regulates epithelial organogenesis throughout development.

PLoS biology

Landsman L, Nijagal A, Whitchurch TJ, Vanderlaan RL, Zimmer WE, Mackenzie TC, Hebrok M

A mouse model of in utero transplantation.

Journal of visualized experiments : JoVE

Nijagal A, Le T, Wegorzewska M, Mackenzie TC

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice.

The Journal of clinical investigation

Nijagal A, Wegorzewska M, Jarvis E, Le T, Tang Q, MacKenzie TC

Image of the month--quiz case. Gastric duplication cyst.

Archives of surgery (Chicago, Ill. : 1960)

Zaid HB, Rhee SJ, Hirose S, Mackenzie TC

Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single institution.

Journal of pediatric surgery

Jancelewicz T, Vu LT, Keller RL, Bratton B, Lee H, Farmer D, Harrison M, Miniati D, Mackenzie T, Hirose S, Nobuhara K

Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice.

Molecular therapy : the journal of the American Society of Gene Therapy

Sabatino DE, Mackenzie TC, Peranteau W, Edmonson S, Campagnoli C, Liu YL, Flake AW, High KA

Impact of continuous intraoperative monitoring on outcomes in open fetal surgery.

Fetal diagnosis and therapy

Keswani SG, Crombleholme TM, Rychik J, Tian Z, Mackenzie TC, Johnson MP, Wilson RD, Flake AW, Hedrick HL, Howell LJ, Adzick NS

Transduction of satellite cells after prenatal intramuscular administration of lentiviral vectors.

The journal of gene medicine

MacKenzie TC, Kobinger GP, Louboutin JP, Radu A, Javazon EH, Sena-Esteves M, Wilson JM, Flake AW

Long-term transgene expression in cardiac and skeletal muscle following fetal administration of adenoviral or adeno-associated viral vectors in mice.

The journal of gene medicine

Bouchard S, MacKenzie TC, Radu AP, Hayashi S, Peranteau WH, Chirmule N, Flake AW

Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes.

Molecular therapy : the journal of the American Society of Gene Therapy

MacKenzie TC, Kobinger GP, Kootstra NA, Radu A, Sena-Esteves M, Bouchard S, Wilson JM, Verma IM, Flake AW

The ex-utero intrapartum treatment.

Current opinion in pediatrics

MacKenzie TC, Crombleholme TM, Flake AW

Engraftment of bone marrow and fetal liver cells after in utero transplantation in MDX mice.

Journal of pediatric surgery

Mackenzie TC, Shaaban AF, Radu A, Flake AW

The natural history of prenatally diagnosed conjoined twins.

Journal of pediatric surgery

Mackenzie TC, Crombleholme TM, Johnson MP, Schnaufer L, Flake AW, Hedrick HL, Howell LJ, Adzick NS

Risk factors for intermediate-term survival after coronary artery bypass grafting.

The Annals of thoracic surgery

Gardner SC, Grunwald GK, Rumsfeld JS, Mackenzie T, Gao D, Perlin JB, McDonald G, Shroyer AL

Large-volume paracentesis in the management of ascites in children.

Journal of pediatric gastroenterology and nutrition

Kramer RE, Sokol RJ, Yerushalmi B, Liu E, MacKenzie T, Hoffenberg EJ, Narkewicz MR

Survival after first esophageal variceal hemorrhage in patients with biliary atresia.

The Journal of pediatrics

Miga D, Sokol RJ, Mackenzie T, Narkewicz MR, Smith D, Karrer FM

The management of prenatally diagnosed choledochal cysts.

Journal of pediatric surgery

Mackenzie TC, Howell LJ, Flake AW, Adzick NS

Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep.

Nature medicine

Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW

35th Annual Meeting of the European Association for the Study of Diabetes : Brussels, Belgium, 28 September-2 October 1999.

Diabetologia

Melander A, Olsson J, Lindberg G, Salzman A, Howard T, Stang P, Lydick E, Emslie-Smith A, Boyle DI, Evans JM, Macdonald TM, Bain J, Sullivan F, Juhl C, Pørksen N, Sturis J, Hollingdal M, Pincus S, Veldhuis J, Dejgaard A, Schmitz O, Kristensen JS, Frandsen KB, Bayer T, Müller P, Dunning BE, Paladini S, Gutierrez C, Deacon R, Valentin M, Grunberger G, Weston WM, Patwardhan R, Rappaport EB, Sargeant LA, Wareham NJ, Khaw KT, Zethelius B, Lithell H, Hales CN, Berne C, Lakka HM, Oksanen L, Tuomainen TP, Kontula K, Salonen JT, Dekker JM, de Boks P, de Vegt F, Stehouwer CD, Nijpels G, Bouter LM, Heine RJ, Bruno G, Cavallo-Perin P, Bargero G, D'Errico N, Borra M, Macchia G, Pagano G, Newton RW, Ruta DA, New JP, Wallace C, Roxburgh MA, Young RJ, Vaughan NJ, Elliott P, Brennan G, Devers M, MacAlpine R, Steinke D, Lawson DH, Decallonne B, Casteels K, Gysemans C, Bouillon R, Mathieu C, Linn T, Strate C, Schneider K, Funda DP, Jirsa M, Kozáková H, Kaas A, Kofronová O, Tlaskalová-Hogenová H, Buschard K, Wanka H, Hartmann A, Kuttler B, Rasmussen SB, Sørensen TS, Markholst H, Petersen JS, Karounos D, Dyrberg T, Mabley JG, Haskó G, Szabó C, Seissler J, Nguyen TB, Steinbrenner H, Scherbaum WA, Cipriani R, Gabriele A, Sensi M, Guidobaldi L, Pantellini F, Cerrito MG, Scarpa S, Di Mario U, Morano S, Ceolotto G, Iori E, Baritono E, Del Prato S, Semplicini A, Trevisan R, Zerbini G, Meregalli G, Asnaghi V, Tentori F, Maestroni A, Mangili R, Marescotti C, Vedovato M, Tiengo A, Tadjieva J, Mankovsky BN, Van Aken S, Raes A, Vande Walle J, Matthys D, Craen M, Hansen HP, Lund SS, Rossing P, Jensen T, Parving HH, Andersen S, Tarnow L, Hansen BV, Trautner C, Haastert B, Ennenbach N, Willich S, Tabák ÁG, Orchard TJ, Spranger J, Preissner KT, Schatz H, Pfeiffer A, Cantón A, Burgos R, Hernández C, Lecube A, Mesa J, Segura RM, Mateo C, Simó R, Fathallah L, Greene DA, Obrosova I, Gilbert RE, Kelly DJ, Cox AJ, Berka-Wilkinson JL, Taylor HR, Panagiotopoulos S, Lee V, Jerums G, Cooper ME, Hitman GA, Aganna E, Ogunkolade WB, Rema M, Deepa R, Shanthi-Rani CS, Barakat K, Kumarajeewa TR, Cassell PG, McDermott MF, Mohan V, Ways K, Bursell S, Devries T, Woodworth J, Alatorre C, King G, Aiello LP, Karisen AE, Pavlovic D, Nielsen K, Jensen J, Andersen HU, Pociot F, Mandrup-Poulsen T, Eizirik DL, Nerup J, Lortz S, Tiedge M, Lenzen S, Lally FJ, Bone AJ, Darville MI, Ho YS, Sternesjö J, Sandler S, Chen MC, Schuit F, Pipeleers DG, Merezak S, Hardikar A, Hoet JJ, Remacle C, Reusens B, Bréant B, Garofano A, Czernichow P, Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Nakano R, Komeda K, Eto K, Tobe K, Kimura S, Kadowaki T, Ide T, Murakami K, Tsunoda M, Mochizuki T, Ozanne SE, Nave BT, Wang CL, Dorling MW, Petry CJ, Koopmans SJ, van der Bent C, Que I, Radder JK, Sebokova E, Sana AK, Klimes I, Ruderman N, Morviducci L, Pastore L, Morelli S, Sagratella E, Zorretta D, Buongiomo A, Tamburrano G, Giaccari A, Martinenghi S, De Angelis GC, Ravasi F, Bifari F, Bordignon C, Falqui L, Kessler A, Dransfeld O, Sasson S, Tomas E, Zorzano A, Eckel J, Thorsby P, Rosenfalck AM, Kjems L, Hanssen KF, Madsbad S, Birkeland KI, Hamilton-Wessler M, Markussen J, Bergman RN, Melki V, Hanaire-Broutin H, Bessières-Lacombe S, Tauber JP, Home PD, Lindholm A, Riis A, Rosenstock J, Schwartz S, Clark C, Edwards M, Donley D, Swift P, Mortensen HB, Lynggaard H, Hougaard P, Cull CA, Neil HA, Frighi V, Manley SE, Holman RR, Turner RC, Steiner G, Davis WA, Weeraratna T, Bruce DG, Davis TM, Vergès B, Duvillard L, Pont F, Florentin E, Gambert P, Benko B, Ljubic S, Turk Z, Granic M, März W, Wollschläger H, Klein G, Neiss A, Wehling M, Huxtable SJ, Saker PJ, Walker M, Frayling TM, Levy JC, O'Rahilly S, Hattersley AT, McCarthy MI, Orecchio A, Giacchini A, Dominici R, Canettieri G, Trinti B, Zani M, Andreoli M, Sciacchitano S, de Silva AM, Whitecross K, Pasco J, Kotowicz M, Nicholson G, Zimmet P, Boyko EJ, Collier GR, Frittitta L, Pizzuti A, Argiolas A, Graci S, Goldfine ID, Bozzali M, Ercolino T, et al

Systemic and renal hemodynamic consequences of manipulation of serum calcium and/or parathyroid hormone in the intact conscious mongrel dog.

Journal of the American College of Nutrition

Zawada ET, Johnson M, McClung D, TerWee J, MacKenzie T

Hemoglobin A1 in renal transplant recipients.

Archives of internal medicine

Zawada ET, Johnson M, Mackenzie T, Sica DA, Muakkassa W, Green SJ, Goldman M

Effect of clonidine therapy on renal hemodynamics in renal transplant hypertension.

Archives of internal medicine

Green S, Zawada ET, Muakkassa W, Johnson M, Mackenzie T, McClanahan M, Graybill A, Goldman M