Division of Immunology, Department of Pediatrics, Boston Children’s Hospital
Immunology has been a central focus of the Department since Charles A. Janeway, MD took the position of Physician-in-Chief in 1946 and, with David Gitlin, pioneered the use of intravenous immune globulin. The Division of Immunology was created in 1968, led by Fred Rosen, MD with a separate Division of Allergy that was headed since 1976, by Raif Geha, MD. The two merged in 1986 under Geha, now the longest-serving Division Chief in Boston Chidren’s Hospital (BCH) history. Since its inception, the Division has been an international front-runner in the field of Pediatric Allergy & Immunology, credited with groundbreaking advances in the molecular, cellular and genetic delineation of a wide range of immunodeficiency syndromes. The Division has attained distinction in Allergy as well. Its investigators have identified dysfunction of regulatory T cells as the basis of tolerance breakdown in food allergy, demonstrated interactions of the microbiome with the gut immune system and dissected pathways of pathogenesis of atopic dermatitis. The Division’s leadership in scientific discovery is matched by its preeminence in clinical care. It is the largest clinical Division of Immunology in the nation with 35,000 patient visits annually. Patients with complex disorders of immune function are referred from around the world for evaluation by its physicians, who are also leaders in NIH-sponsored multicenter studies of the pathogenesis and treatment of allergic and immunologic disorders. A robust educational program, centered around an NIH T32 training grant, fills out the missions of the Division. The incumbent of the Chief position will assume responsibility for leadership, strategic coordination and advancement of all of the clinical, research and training activities in the Division.
Clinical Programs: Unique within the Department of Pediatrics at BCH in covering three independent clinical subspecialties (Allergy & Immunology, Pediatric Rheumatology and Dermatology), the Division provides care for about 35,000 ambulatory visits annually along with inpatient care and consultation for 500 patients, making this, by a wide margin, the biggest such Division in Pediatrics nationally ($22M Annual Clinical Revenues). Under the leadership of Hans Oettgen, MD, PhD (Associate Chief), along with Andrew MacGinnitie, MD, PhD (Clinical Director), the clinical programs have seen dramatic expansion over the past three decades and now, in addition to offering services at the Longwood campus of BCH, offer full service clinics at six satellite locations ranging from Peabody in the North to Milford in the West and New Bedford on the South coast. Further extending the geographic range of service, rheumatologists provide care for children at the University of Massachusetts Medical Center and dermatologists cover consultations at Bay State Medical center via telemedicine. On the Longwood campus, clinics are now open three Saturdays and several evenings every month. Each of the subspecialties has grown over the past decade, notably including an increase from 2 to 7 FTE in Dermatology for which pediatric-trained subspecialists are quite rare and recruitment is particularly challenging. The clinical staff includes 45 MDs, 4 RN-PNPs, 15 RNs and 30 administrative and support personnel. Several specialized integrated
multispecialty clinics are offered by the Division, many developed recently. These include a Food Allergy Center, Aerodigestive Disorders Program, Eosinophilic Gastrointestinal Diseases Center, High Risk Asthma Clinic, Atopic Dermatitis Center, Samara Turkel Rheumatology Center, Immune Dysregulation Clinic, Autoimmunity and Dermatology clinic, Pediatric Oncology Dermatology clinic (DFCI), Autoinflammatory Diseases clinic and, under development, a multi-specialty lupus clinic.
Basic Research: The laboratories of the Division occupy the 10th floor of the Karp Family research building. In contrast to the many other less clinically-oriented Immunology programs at HMS, the unifying theme of the research groups in the BCH Division of Immunology is a focus on the most important research questions seeded by clinical challenges in Allergy, Immunology, Rheumatology and Dermatology. Areas of investigation under the senior PIs include 1) mechanisms of tolerance breakdown, host- microbiome interactions and effector cell function in food allergy (Chatila, Oettgen, Geha),
2) genomics and mechanisms of primary immunodeficiency disorders (Geha, Chatila), 3) mechanisms of skin inflammation in atopic dermatitis (Geha) and 4) innate immune system receptors and signaling (Zanoni). Several Assistant Professors, most currently on or recently funded by NIH K-awards, are being supported to develop independent research programs. Their main themes are 1) the genetic basis of immunodeficiency (Chou), 2) monocyte development and function (Lee), 3) pathogenesis of atopic dermatitis and its connection with food allergy (Leyva-Castillo), 4) genomics of arthritis and lupus (Janssen) and 5) synovial regulatory T cell function in arthritis (Henderson). The Karp 10 Immunology investigators, who have overlapping areas of interest and complementary areas of technical expertise, are highly collaborative and the new investigators receive tremendous support and guidance from the senior PIs.
Division scientists have made a number of high impact discoveries. Some representative examples are cited here. Talal Chatila, MD and his team recently reported that a defined consortium of gut microbiota acts on intestinal immune cells in a Toll like receptor- mediated pathway, to induce a specialized RORgT+ type of regulatory T cells that control food allergy (Nat Immunology, 2019). The same investigators also recently uncovered the basis of the severe asthma phenotype conferred by the Q576R genetic variant of the IL-4 receptor alpha chain (also originally discovered by Chatila, N Engl J Med, 1997). They found that Q576R introduces a consensus Grb2-binding site, linking the receptor to transcriptional induction of genes leading to proinflammatory IL-17-dominated phenotype (Nat Medicine, 2016). In a series of elegant studies, Raif Geha, MD and colleagues have defined the cellular and molecular events in which a combination of skin injury (scratching) and cutaneous allergen exposure leads to atopic dermatitis. Many children with atopic dermatitis also have food allergy and the Geha group recently provided the first demonstration of a compelling immunological basis for this link, showing that IL-33 from injured keratinocytes acts together with IL-25 from intestinal tuft cells to activate innate immune cells (ILC2) which, in turn, promote mast cell expansion (Immunity, 2019). The Geha and Chou groups have led the field in identifying novel genetic mutations underlying immunodeficiency including recently a TFR1 mutation (combined immunodeficiency) 4-1BB (EBV driven lymphoproliferation) IFNRA (CMV infection) RAC2 gain of function mutation, RELA (autoinflammatory disease) PI3KCD loss of function (hypogammaglobulinemia) (combined immunodeficiency) MYD88 truncation (BCG adenitis and neutropenia), c-Rel deficiency (combined immunodeficiency) STAT2 mutation (hemophagocytic lymphohistiocytosis) and ITPKB (severe combined immunodeficiency). The Oettgen lab has demonstrated that IgE-mediated mast cell activation not only results in immediate allergic reactions, as has long been understood, but also provides a critical pool of IL-4 that consolidates and sustains type 2 immune responses in mucosal tissues (Immunity, 2014). The clinical impact of this allergy- amplifying role of IgE is now being evaluated in humans by Oettgen together with Wanda Phipatanakul in the NIH PARK study in which young children are given anti-IgE to prevent allergic sensitization and the onset of asthma. Michiko Oyoshi, PhD’s lab investigates mechanisms of maternal à fetal tolerance transmission in food allergy and has recently found that IgG:allergen immune complexes transmitted via breast milk and transported by the neonatal Fc receptor, FcRN, confer tolerance to mouse pups (J Exp Med, 2018). Ivan Zanoni, PhD and colleagues have reported several high impact observations regarding innate immunity, including a demonstration that CD14 controls endocytosis of TLR4 and facilitates TLR-independent cellular activation by LPS (Cell, 2011). More recently Zanoni has focused on the roles of type III interferons in intestinal immune homeostasis and has described IFN-l regulation of neutrophil functions by non- transcriptional mechanisms (Nat Immunology, 2017).
Clinical and Translational Research: Clinical research has blossomed in the Division over the past two decades especially in the areas of asthma, food allergy and rheumatologic disorders. Wanda Phipatanakul MD, MPH, has developed a leading center of asthma research ($6.9M annual NIH support, including 3 U01’s and 1 R01). Having skillfully fostered a strong alliance with the Boston Public School system, she and her team have gained access to students’ classrooms as well as their homes, allowing large-scale groundbreaking studies on the contributions of defined urban home and school allergen and toxin exposures on asthma onset and morbidity. The center is a site for numerous NIH multi-center studies including the AsthmaNet and SICAS (School Inner City Asthma Study) programs. In addition, several large NIH sponsored treatment and prevention trials have been run from this center. This has benefited the entire Division, providing fruitful opportunities for mechanistic translational studies by basic science PI’s in the Division. One such first-of-kind trial in the prevention of asthma applies a strategy of IgE blockade (Oettgen, mechanistic studies). Other innovative and high-impact studies include an ongoing trial of IL-4 receptor blockade in a genotype-stratified trial enrolling children harboring a genetic variant of the receptor (Q576R) associated with severe disease, originally discovered by Talal Chatila, MD in the Division (Chatila, mechanistic studies), and investigations of the association of the same variant with atopic dermatitis (Geha and Leyva-Castillo, mechanistic studies). In food allergy research, Division investigators have pioneered strategies for oral immunotherapy, including adjunctive use of anti-IgE (omalizumab) (Schneider and Umetsu) and establishing safety and efficacy of the first peanut allergy products likely to receive FDA approval including an OIT formulation (Rachid, Chatila, mechanistic studies) and an epicutaneous patch (Schneider). A highly innovative strategy for reversing established food allergy, fecal microbial transfer, is now in the clinic in Phase I trials (Rachid, Chatila) in a Harvard- Broad-MIT sponsored project. This is an offshoot of studies by Rachid and Chatila with collaborators at the BWH Microbiome Center showing that a defined consortium of bacteria can prevent and/or reverse food allergy in mice. The first pediatric trials of IL-4 receptor blockade in atopic dermatitis are being done in the Division (Schneider). In Rheumatology, ongoing translational investigations include studies to characterize regulatory T (Treg) cell dysfunction in systemic JIA and oligoarticular JIA (Henderson, Chatila, Nigrovic) and mechanistic characterization of a recently described cause of CNS vasculitis and stroke in children, adenosine deaminase 2 deficiency (Lee).
Scholarship: An overview of the published output of its investigators during the preceding five years prepared for last year’s Scientific Advisory Committee (SAC) Review of the Division demonstrated the aggregate impact of their research with numerous papers in the most influential journals including NEJM (6), JAMA (4), Nature (2), Science (3), Immunity (8), Nature Medicine (2), Nature Immunology (2), JCI (6), Blood (12), JEM (11) and PNAS (5). In addition, more than 100 papers were published in the most prestigious journal of the subspecialty, the Journal of Allergy and Clinical Immunology (impact factor 14.2). In terms of published output, this division is without peer in Pediatric Immunology Divisions in the U.S.
Training and Education: The Division of Immunology offers three clinical fellowships: Pediatric Dermatology (Liang, PD), Allergy & Immunology (Schneider, PD) and Pediatric Rheumatology (Lo, PD). Each is viewed as among the preeminent training programs in its specialty in the U.S. In addition, Jennifer Huang in the Division serves as overall PD for the Harvard Combined Dermatology residency, anchoring that nationally highly-ranked residency in the Division as well. The Allergy & Immunology and Pediatric Rheumatology fellowships each include 2-3-year research components during which trainees’ salaries are funded by a 9-slot NIH T32 (Oettgen, PI) now in its 35th year (Geha, founding PI). The T32 attracts the most talented and research- oriented applicants, many holding MD, PhD degrees. While many trainees are paired with mentors within the Division, the grant encourages training with T32 faculty members throughout Harvard, so far including, HMS, BIDMC, MGH, HSPH and BWH. More than 90% of the graduates of this program have remained in academia, many now serving in major leadership positions including Division and Department Chiefs as well as Editors-in-Chief in the U.S. and internationally. Faculty plays a major role in the training of residents in the Boston Combined Residency in Pediatrics and serve as faculty and/or leaders in several HMS courses.
International outreach and collaborations: In an effort to identify novel genetic causes of immunodeficiency the Division established ten years ago the International Consortium for Immune Deficiency (ICID). ICID is co-directed by Raif Geha and Janet Chou. It has 36 collaborating centers spread over North Africa, The Middle East, Southern Europe, and South America. These collaborations foster scientific discovery, and make referrals to BCH of patients with rare immunodefciencies who may undergo bone marrow transplantation or become subjects in gene therapy programs. Patients encountered via CID are an invaluable resource for our training program.
Clinical and Molecular Immunology Laboratories: Craig Platt, MD, PhD, an immunologist in the Division trained in the Geha lab, oversees the execution and strategic development of complex laboratory tests including flow cytometric and functional analyses run in the BCH Department of Laboratory Medicine’s CLIA-certified Immunology lab. For patients with uncharacterized immunodeficiency syndromes, the Division under the leadership of Dr. Janet Chou offers state-of-the-art genetic and functional evaluation in a research setting with a pipeline starting with rapid sequencing of more than 300 genes known to be linked to immunodeficiency followed, if the screen is negative, by whole exome sequencing and in-house bioinformatic analysis of the exome. For all mutations identified in the research lab, CLIA-approved Sanger sequencing (for positive DNA variants) or whole exome analysis is sent out to verify the results. This capability for efficient yet deep immunological evaluation has been a major draw for international referrals, and variants identified in this lab account for six of twelve new mutations reported in the international literature just this past year.
Budget: The wide scope of clinical, scientific and educational activities of the Division is supported by a diverse array of resources. Total operating funds are $37M, distributed among $22M clinical revenue, $12M Grants and $3M endowment income. The NIH research grant portfolio includes 13 R01, 4 U01 and 1 U19 grants. NIH training grants in the portfolio include a T32 (9 slots, $601K) along with 2 K08 and 2 K23 awards. Pharma awards from Genentech, Aimmune, ThermoFisher and others support ongoing clinical and related mechanistic studies. The Division has actively cultivated relationships with philanthropists from individuals and foundations including the David and Denise Bunning Foundation for Food Allergy Research, The Food Allergy Science Initiative, The Perkin Fund, The Samara Turkel Fund and others. Four HMS chairs and one BCH chair support senior Division faculty. Four investigatorships, smaller endowed funds awarded for two- year periods, help promote the emerging research programs of young investigators in the Division. The division has also accumulated a substantial surplus from its clinical income that has been instrumental in recruiting faculty.
Qualifications: The incumbent Chief will be an internationally recognized senior physician investigator specialized in Allergy & Immunology. S/he will have demonstrated an outstanding record in basic or translational research and have the breadth of scientific knowledge and insight to shepherd the academic mission of the Division. It will be critical for the incoming leader to also have deep experience and demonstrated proficiency in administration as well as the ability to align goals among the diverse clinical programs and to integrate the clinical, research and educational activities of the Division. The incumbent should have the skills needed to sustain and expand the current federal funding portfolio while actively fostering relationships with private philanthropists, foundations and pharma sources. Finally, the successful candidate must be an outstanding individual who is able to work collegially with the clinicians and scientists in his or her charge and to foster collaborations and interactions among Division faculty members as well as with the broader Boston Children’s and Harvard Medical School faculties.