The Pursuit of Basic Immunologic Studies
Leads to Novel Immune Therapies

For all publications, including the most recent,  please see Engleman Lab Publications.

Alloantibody-based Immunotherapy for Cancer

Manipulation of Dendritic Cells in the Treament of Cancer

Regression of Lung Metastasis after treatment at Day 30

Primary tumor size in mice with or without treatment

We have recently discovered a novel approach to the treatment of solid tumors in which dendritic cells in tumors are armed and activated by tumor-binding antibodies in combination with dendritic cell stimuli. This approach overcomes the local immunosuppressive milieu and results in extremely potent anti-tumor immunity that can eradicate tumors, including metastases, in mice.

Allogenic IgG in tumor cells

Treatment of Neurologic Diseases

Targetting Microglia in the Treatment of Neurologic Diseases

Development of Microglia

Pictures of microglia development (left) and FACS analysis of microglia (right) Proposed role of microglia in neurodegeneration

Small -drug molecule targetting Microglia

Most chronic neurodegenerative diseases are believed to be caused by, and limited to, injury to neurons. However, our studies of mouse models of Parkinson’s disease and Alzheimer’s disease have revealed a specific signaling abnormality in microglia, macrophage-like resident cells of the brain, that results in chronic release of inflammatory mediators. Moreover, we have reversed this abnormality and ameliorated neurologic symptoms in these diseases with a novel small drug-like molecule, that crosses the blood brain barrier and specifically targets microglial dysfunction in these diseases.

Neurodegeneration

Immunobiology of microglia, the resident innate immune cells in the central nervous system. They originate from primitive hematopoietic stem cells and populate the brain during development. Microglia are the only type of immune cells that reside in the brain at steady state. Besides their evolving roles in brain function and development, little is known about their participation in various CNS pathologies such as neurodegeneration, cancer, and infection  Our laboratory is using cutting edge immunological and bioenergetic tools to dissect their roles in normal physiological contexts as well as in a wide range of CNS diseases

Parkinson's Disease Model

Drug treatment inhibits microglial TNF-a production and ameliorates motor dysfunction in the MPTP mouse model of Parkinson’s disease.

(A)   TNF-a production of microglia from healthy animals, MPTP intoxicated animals and those treated with our small drug-like molecule.

(B)   Nest building skills of healthy animals, MPTP intoxicated animals and those treated with our small drug-like molecule.

(C)   Tyrosine hydroxylase staining in the substantia nigra of of healthy animals, MPTP intoxicated animals and those treated with our small drug-like molecule.

 

Retinoic Acid as a Therapeutic Agent

Manipulating Immune System in the Colon with Retinoic Acid

Microscopic image of mouse colon

"Myenteric plexi of a mouse colon. Enteric glia are imaged in green with a molecule indicating activation in red."   

Modulation of atRA impacts tumor burden in colitis -associated cancer

We have discovered that colorectal cancer (CRC) is associated with a deficit in colonic retinoic acid, the principal metabolite of Vitamin A, which is caused mainly by excessive breakdown of the molecule.  As a result of this deficit, local intestinal immunity is compromised. Remarkably, in mouse models of CRC, treatment with retinoic acid or an inhibitor of the main enzyme that catabolizes retinoic acid reverses this defect and markedly reduces tumor burden through the induction of tumor-reactive CD8 cytotoxic T cells. Importantly, the frequency of CD8 T cells in human CRC is an accurate predictor of clinical course, and there is an inverse correlation between the concentration of the enzyme that catabolizes retinoic acid and CD8 T cell frequency in CRC

Plasmacytoid Dendritic Cells

Morphologic Differences Between Plasmacytoid DC subsets

Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) are one of the two main populations of dendritic cells. They are known as type I IFN-producing cells which play important roles in the immune response against viral infection. In our study, we identified a novel human pDC subset. Despite its low frequency, this pDC subset can be consistently found in normal human blood. Unlike regular pDCs, this pDC subset secretes very little amount of type I IFNs upon stimulation but shows higher capability in producing other inflammatory cytokines. Further characterization of these pDCs shows that they have distinct morphology, phenotype and functions.

Immune System Reference Mapping

System Wide Analysis of the Immune system using Mass Cytometry

Generation of Immune System Map

Unsupervised force-directed layout analysis of T cells from different anatomical locations in the mouse. Top: Layout is colored by sample of origin to identify population distribution across samples. Bottom: Layout is colored on a heatmap scale to visualize protein expression across the T cell landscape.