Tippi Mackenzie, MD

Professor
Department of Surgery
+1 415 476-2479

Stem Cell Transplantation. Our lab studies in utero hematopoietic stem cell transplantation (IUHCT) with the goal of elucidating mechanisms of engraftment and tolerance induction. Transplantation of allogeneic stem cells into the early gestational fetus can overcome the limitations of postnatal bone marrow transplants, including rejection and graft vs host disease. We showed in a mouse model that maternal T cells are the main barrier to engraftment (PMC3026737), suggesting that IUHCT could be improved by transplanting maternal stem cells. We found that tolerance induction after IUHCT depends on both direct and indirect antigen presentation (PMC3668492) and is secondary to thymic deletion. In a mouse model, we improved engraftment with in utero depletion of fetal hematopoietic stem cells (by injecting an antibody against the cKit receptor) to increase the HSC niche for donor cell engraftment, with minimal toxicity (PMC4126335). Most recently, we demonstrated that IUHCT can result in engraftment of donor-derived microglia in the brain, which has important implications for the treatment of lysosomal storage disorders (PMID: 32102934).

Following these advances in the mouse model, we opened a Phase I clinical trial for IUHCT in patients with alpha thalassemia major (NCT02986698). Fetuses diagnosed with alpha thalassemia major receive hematopoietic stem cells that have been harvested from the mother, concomitantly with a blood transfusion to treat the fetal anemia. The hope is to induce tolerance to the maternal cells to allow the mother to be a viable donor for stem cell transplantation to treat the baby after birth. To date, two patients have completed the trial, both of whom safely received IUHCT and are now thriving toddlers!

Maternal-Fetal Tolerance. Our lab studies mechanisms of maternal-fetal tolerance with the goal of improving fetal intervention outcomes and preventing immune-mediated complications of pregnancy. During gestation, the fetus exists in a unique state of immune tolerance with the mother; we now understand that tolerance in both directions (maternal tolerance of the fetus (PMC4268439) and vice versa) is important for a healthy pregnancy. We have shown that in the context of preterm labor, the fetal immune system can be activated against maternal antigens, which triggers a cascade of events culminating in preterm uterine contractions (PMC6449052). We are now trying to understand changes in the microbiome (PMC7159194) and other antigens involved in this aberrant immune response so that we can develop targeted therapies for preterm birth. We are also fascinated by the role of congenital anomalies such as gastroschisis (PMC4977025PMC6715406) in altering fetal immune development, with possible consequences on preterm birth and postnatal health.

Our lab is also investigating the role of autoimmune regulator gene (Aire) in supporting maternal-fetal tolerance. Aire prevents autoimmunity by inducing tolerance to self-antigens. A healthy pregnancy requires tolerance to a unique set of maternal self-antigens: those arising from the decidua, placenta, and embryo. We are investigating whether maternal self-tolerance to pregnancy-associated antigens protects a pregnancy and how the Aire gene may be involved. This work is relevant to common pregnancy complications such as miscarriage and intrauterine growth restriction, both of which are often associated with autoimmunity.

Fetal Molecular Therapies. Advances in molecular therapies such as gene therapy and gene editing have led to postnatal clinical trials aiming to treat congenital genetic diseases such as hemoglobinopathies, coagulopathies, neuromuscular degenerative diseases, and lysosomal storage disorders. Our team and collaborators are working toward applications of these therapies in the prenatal setting to treat fetuses with genetic diseases (PMC6453510).

The fetal environment offers multiple potential advantages over postnatal treatment for some congenital genetic diseases. First, the unique fetal immune environment may allow us to induce tolerance to a missing protein such as a clotting factor or a lysosomal enzyme. Second, it may be possible for systemically injected medication to reach cells in the fetal brain before the blood-brain barrier closes. Finally, fetal therapy may prevent organ-specific disease manifestations during a critical window of tissue development. A goal of the MacKenzie lab is to develop safe and effective fetal molecular therapies in translational animal models and to lead the way in developing responsible fetal molecular therapy clinical trials to treat patients with severe genetic diseases before birth.

Research Summary: 
Stem cell transplantation, maternal-fetal tolerance, and fetal molecular therapies

Websites

Publications: 

Detection of microbial cell-free DNA in maternal and umbilical cord plasma in patients with chorioamnionitis using next generation sequencing.

PloS one

Witt RG, Blair L, Frascoli M, Rosen MJ, Nguyen QH, Bercovici S, Zompi S, Romero R, Mackenzie TC

Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII.

Science translational medicine

Nguyen QH, Witt RG, Wang B, Eikani C, Shea J, Smith LK, Boyle G, Cadaoas J, Sper R, MacKenzie JD, Villeda S, MacKenzie TC

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

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