Legends of Allergy and Immunology: Donald Y. M. Leung

Abstract

This issue is honoring Donald Leung, who is best known for his work in atopic dermatitis (AD), along with many other contributions in allergy and immunology. Donald was born October 1, 1949 in New York City. He received his PhD in biochemistry and MD at the University of Chicago. He subsequently went on to residency and fellowship at Children’s Hospital Boston where he continued as a faculty member at Harvard Medical School until 1989. With Dr. Raif Geha, they studied the role of Th2 cells in allergic responses and he began work in Kawasaki’s disease and AD. He made many relevant discoveries regarding Kawasaki Disease including its treatment with intravenous gamma globulin treatment for which he received a ten year NHLBI MERIT award.

I first met Donald, in 1988, when we discussed the concept of steroid resistant asthma and similarities to AD, the beginning of our collaboration. He came to National Jewish Health, in 1989, as Division Head for Allergy and Immunology and then Professor of Pediatrics. He was named Director for the NIH funded Clinical Translational Research Center at National Jewish Health. He has been the principal investigator on over 35 NIH research grants for the past 30 years, mainly involving food allergy (FA) and AD.

Dr. Leung has contributed greatly to the scientific understanding of immune responses in AD and FA (Table 1). AD often precedes the occurrence of FA and recent research suggests that FA may occur via sensitization through environmental food allergens that penetrate the AD skin. Dr. Leung’s group was the first to demonstrate the presence of IL4 and IL-13 in AD skin (Figure 1A).¹ Importantly, he led the first controlled multi-center study (Figure 1B) demonstrating the safety and effectiveness of anti-IgE in reducing severity of clinical peanut reactions in peanut allergic patients.²

Table 1.

Major advances in allergy and immunology attributed to Donald Leung.

1983	Characterized the T cell infiltrate in AD skin using monoclonal antibodies to different T cell subsets.
1994	Demonstrated the presence of Type 2 cytokines in nonlesional AD skin and acute AD skin.
1995	Identified the expansion of skin homing T cell responses to food in patients with food-induced eczema.
2002	Demonstrated IL4 and IL13 predisposed to S. aureus infection in AD.
2003	First study showing anti-IgE prevents peanut induced allergic reactions.
2007	Led research effort demonstrating Th2 cytokines subverted skin barrier function.
2013	Discovered the molecular mechanism and cofactors for corticosteroid resistance in various clinical settings and the role of the microbiome in directing response to steroids.
2016	Reported the appearance of epidermal thymic stromal lymphopoietin at 2 months of age prior to the clinical development of AD at 2 years of age.
2018	Use of non-invasive skin tape stripping approach to demonstrate epidermal lipid, protein and transcriptome profiles in AD.

Figure 1A.

First demonstration of increased IL-4 expression in atopic dermatitis skin (from reference 1).

Dr. Leung’s lab has focused on host responses in AD patients that are predisposed to S. aureus colonization and infection. This is relevant to FA as FA is associated with increased S. aureus colonization. AD patients prone to S. aureus colonization and infection have polarized Th2 responses in their skin. Once S. aureus binds to the skin, his group demonstrated that AD skin has difficulty eradicating this microbe due to reduced levels of keratinocyte derived antimicrobial peptides.³ They also identified the Staphylococcal virulence factors, including superantigens, lipoteichoic acid, and cytotoxins, contributing to AD pathobiology and other immunologic skin diseases. They demonstrated the role that these virulence factors play in activating T cells and keratinocytes contributing to immune and inflammatory skin responses in AD.

Their research group also studied the cross talk between cytokines expressed during the AD immune response and subversion of local innate responses and effects on epidermal skin differentiation including the downregulation of skin barrier proteins such as filaggrin which are a more common cause of low filaggrin levels in AD skin than filaggrin mutations.⁴ They demonstrated the role of Th2 cytokines in modulating IgE responses and subverting the innate immune response pioneering the rationale for studies using humanized monoclonal antibodies against the IL-4 receptor alpha to block Th2 cytokine action and remarkable reduction in skin severity of AD.

Using a minimally invasive skin tape stripping transcriptome method, they demonstrated that only 50% AD is associated with high Type 2 immune activation. They also showed that there was an accumulation of short chain lipids in AD that was driven by IL-13 suppression of lipid elongase activity.⁵ The importance of Type 2 cytokines in driving AD was demonstrated in a birth cohort study through the appearance of epidermal thymic stromal lymphopoietin at 2 months of age prior to the clinical development of AD at 2 years of age.⁶

Dr. Leung also discovered the distinct cytokine profiles and inflammatory response of patients with steroid sensitive vs steroid resistant asthma including the molecular mechanism and cofactors for corticosteroid resistance and the role of the microbiome in directing response to steroids.⁷

In 1998, Donald became the Editor-in-Chief for the Journal of Allergy and Clinical Immunology and remained in that position until 2015. He worked hard to make it one of the most highly cited specialty journals in medicine. Donald coaxed Hal Nelson and I to assist as Deputy Editors. Donald took on the job with a passion, spending many hours developing innovative sections, stimulating high profile investigators to contribute, diversifying the articles, and rapidly increasing the visibility of the journal. We introduced new topics to the journal, including genetics, cohort studies, network studies, and the era of personalized medicine. Donald was always generating new ideas and bringing on new talent.

Dr. Leung has had more than 700 publications, has a H index of 111 and was recognized by ISI as being one of the most highly cited authors in immunology. He has received many awards including the E. Mead Johnson Award for Outstanding Research in Pediatrics, American Academy of Allergy, Asthma and Immunology (AAAAI) Distinguished Service Award, AAAAI Establishment of The Donald Leung/JACI Editors AAAAI Foundation Career Development Award, and in 2018 the American Academy of Allergy, Asthma and Immunology Distinguished Scientist Award for contributions to our understanding of AD (Figure 2).

Figure 2.

Donald Leung receiving the American Academy of Allergy, Asthma and Immunology Distinguished Scientist Award for seminal work in atopic dermatitis.

Donald has been the Principal Investigator of the NIH/NIAID Atopic Dermatitis Research Network (ADRN) for more than 15 years. His expertise into the pathobiology of AD including investigation in filaggrin breakdown products, skin lipidomics, transcriptome and proteomics will be important for his ongoing research in young infants. He also serves as the Denver PI for the Consortium of Food Allergy Research.

He continues to integrate the role of immunology, allergy, infection, and biologic mechanisms including genetics in understanding AD and providing insights into management. He developed the textbook, Pediatric Allergy: Principles and Practice, now entering its fourth edition. He is supported by his wife, Susan Leung, RN, who is his clinical research manager, along with numerous collaborators. We all look forward to more amazing contributions from this legend in allergy and immunology.

Figure 1B.

First demonstration that treatment of peanut allergic patients with anti-IgE can reduce peanut induced allergic reactions (from reference 2).