John Yi

Overview:

I am an immunologist, with a focus to characterize the immune system in response to infectious and non-infectious diseases including cancer, HIV, autoimmune disease, and transplantation. My goals are to identify novel biomarkers/immune signatures that clinicians can utilize to diagnosis, predict disease outcomes, and determine patients' response to treatment. 

Positions:

Adjunct Assistant Professor in the Department of Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2010

University of Alabama Birmingham

Grants:

Magnetically directed single cell transcriptome analysis in HIV latency

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Feasibility of using Bortezomib-based immunosuppressive approach to deplete anti-AAV antibodies in mice

Administered By
Pediatrics, Medical Genetics
Awarded By
Asklepios BioPharmaceutical, Inc.
Role
Co Investigator
Start Date
End Date

VTEU Task D Option 2 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

VTEU Task D Option 3 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

VTEU Task D Option 4 Protocol FY.2015.A4D14.0033

Administered By
Duke Human Vaccine Institute
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Publications:

Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease.

Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals' native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual's native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient's relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.
Authors
De Groot, AS; Desai, AK; Lelias, S; Miah, SMS; Terry, FE; Khan, S; Li, C; Yi, JS; Ardito, M; Martin, WD; Kishnani, PS
MLA Citation
De Groot, Anne S., et al. “Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease.Front Immunol, vol. 12, 2021, p. 636731. Pubmed, doi:10.3389/fimmu.2021.636731.
URI
https://scholars.duke.edu/individual/pub1487554
PMID
34220802
Source
pubmed
Published In
Frontiers in Immunology
Volume
12
Published Date
Start Page
636731
DOI
10.3389/fimmu.2021.636731

Cellular changes in eculizumab early responders with generalized myasthenia gravis.

Eculizumab (ECU), a C5 complement inhibitor, is approved to treat acetylcholine receptor autoantibody positive generalized myasthenia gravis (AChR MG). The clinical effect of ECU relies on inhibition of the terminal complement complex; however, the effect of ECU on lymphocytes is largely unknown. We evaluated innate and adaptive immunity among AChR MG patients (N = 3) before ECU and ≥3 months later while on stable therapy, and found reduced activation markers in memory CD4+ T cell subsets, increased regulatory T cell populations, and reduced frequencies of CXCR5+HLA-DR+CCR7+ Tfh subsets and CD11b+ migratory memory B cells. We observed increases within CD8+ T cell subsets that were terminally differentiated and senescent. Our data suggest complement inhibition with ECU modulates the adaptive immunity in patients with MG, consistent with preclinical data showing changes in complement-mediated signaling by T- and antigen-presenting cells. These findings extend our understanding of ECU's mechanism of action when treating patients with MG.
Authors
Li, Y; Yi, JS; Howard, JF; Chopra, M; Russo, MA; Guptill, JT
MLA Citation
Li, Yingkai, et al. “Cellular changes in eculizumab early responders with generalized myasthenia gravis.Clin Immunol, vol. 231, Oct. 2021, p. 108830. Pubmed, doi:10.1016/j.clim.2021.108830.
URI
https://scholars.duke.edu/individual/pub1495084
PMID
34450290
Source
pubmed
Published In
Clin Immunol
Volume
231
Published Date
Start Page
108830
DOI
10.1016/j.clim.2021.108830

C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates.

Sensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury.
Authors
Schmitz, R; Fitch, ZW; Schroder, PM; Choi, AY; Manook, M; Yoon, J; Song, M; Yi, JS; Khandelwal, S; Arepally, GM; Farris, AB; Reis, ES; Lambris, JD; Kwun, J; Knechtle, SJ
MLA Citation
Schmitz, Robin, et al. “C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates.Nat Commun, vol. 12, no. 1, Sept. 2021, p. 5456. Pubmed, doi:10.1038/s41467-021-25745-7.
URI
https://scholars.duke.edu/individual/pub1497202
PMID
34526511
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
5456
DOI
10.1038/s41467-021-25745-7

Immune cell profiling in the joint following human and murine articular fracture.

OBJECTIVE: Human and in vivo animal research implicates inflammation following articular fracture as contributing to post-traumatic arthritis. However, relevant immune cell subsets present following injury are currently undefined. Immunophenotyping human and murine synovial fluid may help to identify immune cell populations that play key roles in the response to articular fracture. METHODS: Immunophenotyping by polychromatic flow cytometry was performed on human and mouse synovial fluid following articular fracture. Specimens were collected in patients with closed ankle fracture at the time of surgical fixation and from C57BL/6 mice with closed articular knee fracture. Immune cells were collected from injured and uninjured joints in mice via a novel cell isolation method. Whole blood samples were also collected. Immunohistochemistry (IHC) was performed on mouse synovial tissue to assess for macrophages and T cells. RESULTS: Following intra-articular fracture, the prominent human synovial fluid immune cell subset was CD3+ T cells, containing both CD4+ and CD8+ T cells. In mice, infiltration of CD45+ immune cells in synovial fluid of the fractured limb was dominated by CD19+ B cells and CD3+ T cells at 7 days after intra-articular fracture. We also detected adaptive immune cells, including macrophages, NK cells, dendritic cells and monocytes. Macrophage and T cell findings were supported by IHC of murine synovial tissue. CONCLUSIONS: Determining specific cell populations that mediate the immune response is essential to elucidating the chain of events initiated after injury and may be an important step in identifying potential immune signatures predictive of PTA susceptibility or potential therapeutic targets.
Authors
Furman, BD; Zeitlin, JH; Buchanan, MW; Huebner, JL; Kraus, VB; Yi, JS; Adams, SB; Olson, SA
MLA Citation
Furman, B. D., et al. “Immune cell profiling in the joint following human and murine articular fracture.Osteoarthritis Cartilage, vol. 29, no. 6, June 2021, pp. 915–23. Pubmed, doi:10.1016/j.joca.2021.02.565.
URI
https://scholars.duke.edu/individual/pub1475541
PMID
33640582
Source
pubmed
Published In
Osteoarthritis Cartilage
Volume
29
Published Date
Start Page
915
End Page
923
DOI
10.1016/j.joca.2021.02.565

Reduced plasmablast frequency is associated with seronegative myasthenia gravis.

BACKGROUND: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG. METHODS: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG. RESULTS: An increase in CD19+ CD20- CD38hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004). CONCLUSIONS: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future.
Authors
Guptill, JT; Barfield, R; Chan, C; Russo, MA; Emmett, D; Raja, S; Massey, JM; Juel, VC; Hobson-Webb, LD; Gable, KL; Gonzalez, N; Hammett, A; Howard, JF; Chopra, M; Kaminski, HJ; Siddiqi, ZA; Migdal, M; Yi, JS
MLA Citation
Guptill, Jeffrey T., et al. “Reduced plasmablast frequency is associated with seronegative myasthenia gravis.Muscle Nerve, vol. 63, no. 4, Apr. 2021, pp. 577–85. Pubmed, doi:10.1002/mus.27140.
URI
https://scholars.duke.edu/individual/pub1468619
PMID
33294984
Source
pubmed
Published In
Muscle &Amp; Nerve
Volume
63
Published Date
Start Page
577
End Page
585
DOI
10.1002/mus.27140

Research Areas:

Autoimmune Diseases
Biomarkers, Pharmacological
Cancer
Flow Cytometry
Immunologic Deficiency Syndromes
Immunology
Lungs--Transplantation
Neuromuscular Diseases