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Research Division Faculty


 
 
 
Primary Appointment: Distinguished Professor of Immunology and Microbiology
Member, Program in Structural Biology and Biophysics
 
For the past 10 years my laboratory at National Jewish Health has been in an extended collaboration with members of the Basic and Translational Research Division at the BDC trying to understand the molecular basis CD4+ T cell recognition of pancreatic islet protein epitopes in type 1 diabetes (T1D).  In the last year I have established a satellite lab at the BDC to foster this work and taken on the role of Interim Director of this group until the arrival of Dr. Lori Sussel in 2016 as permanent Director.
My research collaboration with the Basic and Translational Research Division at the BDC has been very productive, especially in our studies on insulin as a primary target from CD4+ T cells in T1D in mouse and man and on chromogranin A (ChgA), another pancreatic protein targeted in T1D in the mouse and perhaps in humans. Our research has shown that the natural peptides derived from these proteins, are targeted by diabetogenic CD4+ T cells in the NOD mouse model of the disease, but are in fact very weak antigens.  We have shown that a few particular amino acids can be added to one end of the insulin peptide or to the other end of the ChgA peptide to increase their potency more than 1000-fold. Working with the laboratory of Dr. Shaodong Dai at National Jewish Health, we were able to use X-ray crystallography to determine the molecular basis for how these additions accomplish this dramatic increase in immunogenicity.  Subsequently, for insulin, experiments by Drs. Nakayama, Gottlieb, Michels, Sosinowski and Davidson, some in collaboration with researchers at the Benaroya Center in Seattle have shown a similar mutational improvement in recognition of the insulin peptide by CD4+ T cells from human patients with type-1 diabetes.
These findings have led us hypothesize that these types of modifications may naturally occur uniquely in the pancreas by a process called transpeptidation accounting for the initiation of T1D in both mouse and man.  Since such a modification creates a “neo-antigen” never seen by the immune system before, the immune system may mistake the peptide for a “foreign” antigen and mount a response.  Testing this hypothesis is a major goal of our present research.

 

BDC Lab Members:
Principal Investigator: John W. Kappler, MD
Instructor: Niyun Jin, MD

Publications

Education:
PhD: Brandeis University (Chemistry)
Fellowship: University of California, San Diego (Immunology)

Please direct inquiries to specific e-mail addresses listed within individual entries. For all other general Research inquiries, please contact: Kathryn Gray, BFA, MA​