Timothy B. Niewold, MD, FACR

Mayo Clinic, Scottsdale, AZ

2009 Genetics, Human Lupus Biology
2016 New Treatment, Dendritic Cells, Cell Signaling

Can we manipulate the body's own immune system - its natural ability to suppress specialized immune cells - to create a new treatment for lupus?

The study and what it means to patients

“Our research aims to identify ways to reduce the numbers of specialized cells called PDCs known to cause inflammation in lupus. Understanding how PDC production is reduced naturally will inform development of new treatments that can suppress these disease-causing cells.”

Summary:

Specialized cells known as plasmacytoid dendritic cells (PDCs), that typically help regulate the immune system, also trigger autoimmune disease when they are activated in lupus. Though many studies have identified factors that increase the inflammation caused by these cells, very little is known about proteins called negative regulators that suppress the activation of PDCs in lupus.

We plan to study two important negative regulators that decrease PDC activation in lupus patients. Crucially, our research will reveal information about how naturally existing molecules suppress PDC activity; this unique and groundbreaking insight could facilitate novel therapies that leverage this natural suppressive capacity.

Technical Summary:

Plasmacytoid dendritic cells (PDCs) are a major source of type I interferon (IFN), and are important pathogenic effector cells in systemic lupus erythematosus (SLE). Though many studies have characterized factors that amplify inflammatory pathways in SLE, the study of negative regulators is equally important and has not been as extensively explored. In this proposal, we plan to study the expression and function of two important immune regulators of PDCs, immunoglobulin like transcript 7 (ILT-7) and blood dendritic cell antigen 2 (BDCA2) to induce tolerogenic PDCs in human SLE. We have two Specific Aims: Aim 1: Assess the functional consequence of decreased expression of ILT-7 and BDCA2 on SLE patient PDCs, and relationship to disease phenotypes. Aim 2: Determine capacity of ILT-7 and BDCA2 to induce tolerogenic DCs in SLE patients, both separately and in combination. The data we generate will identify important patient sub-groups to be targeted, and define which intracellular signaling pathways are interrupted. Aim2 will potentially support a novel dual inhibition therapeutic strategy which would combine ILT-7 and BDCA2 ligation, as it seems unlikely that ligating a single suppressive receptor on the PDC surface will lead to a tolerogenic outcome.

- See more at: http://lupusresearchinstitute.org/lupus-research/grant-recipients/timoth...

Can we manipulate the body's own immune system - its natural ability to suppress specialized immune cells - to create a new treatment for lupus?

The study and what it means to patients

“Our research aims to identify ways to reduce the numbers of specialized cells called PDCs known to cause inflammation in lupus. Understanding how PDC production is reduced naturally will inform development of new treatments that can suppress these disease-causing cells.”

Summary:

Specialized cells known as plasmacytoid dendritic cells (PDCs), that typically help regulate the immune system, also trigger autoimmune disease when they are activated in lupus. Though many studies have identified factors that increase the inflammation caused by these cells, very little is known about proteins called negative regulators that suppress the activation of PDCs in lupus.

We plan to study two important negative regulators that decrease PDC activation in lupus patients. Crucially, our research will reveal information about how naturally existing molecules suppress PDC activity; this unique and groundbreaking insight could facilitate novel therapies that leverage this natural suppressive capacity.

Technical Summary:

Plasmacytoid dendritic cells (PDCs) are a major source of type I interferon (IFN), and are important pathogenic effector cells in systemic lupus erythematosus (SLE). Though many studies have characterized factors that amplify inflammatory pathways in SLE, the study of negative regulators is equally important and has not been as extensively explored. In this proposal, we plan to study the expression and function of two important immune regulators of PDCs, immunoglobulin like transcript 7 (ILT-7) and blood dendritic cell antigen 2 (BDCA2) to induce tolerogenic PDCs in human SLE. We have two Specific Aims: Aim 1: Assess the functional consequence of decreased expression of ILT-7 and BDCA2 on SLE patient PDCs, and relationship to disease phenotypes. Aim 2: Determine capacity of ILT-7 and BDCA2 to induce tolerogenic DCs in SLE patients, both separately and in combination. The data we generate will identify important patient sub-groups to be targeted, and define which intracellular signaling pathways are interrupted. Aim2 will potentially support a novel dual inhibition therapeutic strategy which would combine ILT-7 and BDCA2 ligation, as it seems unlikely that ligating a single suppressive receptor on the PDC surface will lead to a tolerogenic outcome.

- See more at: http://lupusresearchinstitute.org/lupus-research/grant-recipients/timoth...

Can we manipulate the body's own immune system - its natural ability to suppress specialized immune cells - to create a new treatment for lupus?

The study and what it means to patients

“Our research aims to identify ways to reduce the numbers of specialized cells called PDCs known to cause inflammation in lupus. Understanding how PDC production is reduced naturally will inform development of new treatments that can suppress these disease-causing cells.”

 

Summary:

Specialized cells known as plasmacytoid dendritic cells (PDCs), that typically help regulate the immune system, also trigger autoimmune disease when they are activated in lupus. Though many studies have identified factors that increase the inflammation caused by these cells, very little is known about proteins called negative regulators that suppress the activation of PDCs in lupus.

We plan to study two important negative regulators that decrease PDC activation in lupus patients. Crucially, our research will reveal information about how naturally existing molecules suppress PDC activity; this unique and groundbreaking insight could facilitate novel therapies that leverage this natural suppressive capacity.

Technical Summary:

Plasmacytoid dendritic cells (PDCs) are a major source of type I interferon (IFN), and are important pathogenic effector cells in systemic lupus erythematosus (SLE). Though many studies have characterized factors that amplify inflammatory pathways in SLE, the study of negative regulators is equally important and has not been as extensively explored. In this proposal, we plan to study the expression and function of two important immune regulators of PDCs, immunoglobulin like transcript 7 (ILT-7) and blood dendritic cell antigen 2 (BDCA2) to induce tolerogenic PDCs in human SLE. We have two Specific Aims: Aim 1: Assess the functional consequence of decreased expression of ILT-7 and BDCA2 on SLE patient PDCs, and relationship to disease phenotypes. Aim 2: Determine capacity of ILT-7 and BDCA2 to induce tolerogenic DCs in SLE patients, both separately and in combination. The data we generate will identify important patient sub-groups to be targeted, and define which intracellular signaling pathways are interrupted. Aim2 will potentially support a novel dual inhibition therapeutic strategy which would combine ILT-7 and BDCA2 ligation, as it seems unlikely that ligating a single suppressive receptor on the PDC surface will lead to a tolerogenic outcome.


Novel Genes Associated with African-American Lupus

That African-Americans are three times more likely than Caucasians to develop lupus and with greater severity is well-known. But we do not know why. With initial grant support from LRI, researcher Dr. Timothy Niewold at the The Mayo Clinic, Rochester, MN has made great headway in uncovering some of the genes that may predispose African Americans to lupus. In 2011 his work gained particular recognition with several published papers and a sizeable grant from the National Institutes of Health.

Dr. Niewold’s initial proposal hypothesized that African-American patients carry genes that cause them to produce higher levels of interferon-alpha, a critical molecule known to drive lupus progression.

Published in August 2011 issue of Arthritis & Rheumatism, Dr. Niewold’s results showed that interferon-alpha levels are indeed higher in African-American lupus patients. Also stemming from original LRI-funded research, Dr. Niewold’s team had previously discovered differences between Caucasians and African Americans in six genes along the biological pathway involved in producing interferon-alpha.

“By studying the genetics of a multi-gene pathway, we can understand what goes wrong and where in the process we can effectively intervene,” said Dr. Niewold. “Our discovery of these genetic factors affecting the production of interferon-alpha should help us individualize treatment in this disproportionately affected patient group.”

The NIH shares Dr. Niewold’s interest in finding the cause for lupus prevalence and severity among African Americans, awarding him an RO1 grant of $1.95 million to extend his LRI work on a large scale. The five-year study will look deeper into how inherited genetic abnormalities in the interferon-alpha pathway might contribute to lupus in African Americans and other populations.

The goal: information that will enable physicians to individualize and improve treatment for African Americans with lupus.

Select publications:

Influenza vaccination responses in human systemic lupus erythematosus: Impact of clinical and demographic features. Crowe SR, Merrill JT, Vista ES, Dedeke AB, Thompson DM, Stewart S, Guthridge JM, Niewold TB, Franek BS, Air GM, Thompson LF, James JA. Arthritis Rheum. 2011 Aug;63(8):2396-406. doi: 10.1002/art.30388.

Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheum. 2011 Apr;63(4):1044-53. doi: 10.1002/art.30187. Weckerle CE, Franek BS, Kelly JA, Kumabe M, Mikolaitis RA, Green SL, Utset TO, Jolly M, James JA, Harley JB, Niewold TB.

See more here.

Rev. March 2012