Tags Posts tagged with "immune system"

immune system

Peter Westcott, on right, in the lab with technicians Zakeria Aminzada, on left and Colin McLaughlin, center. Photo by Steven Lewis

By Daniel Dunaief

When Peter Westcott was growing up in Lewiston/Auburn, Maine, his father Johnathan Harris put the book “Human Genome” on his bed. That is where Westcott, who has a self-described “obsessive attention to detail,” first developed his interest in biology.

Westcott recently brought that attention to detail to Cold Spring Harbor Laboratory, where he is an assistant professor and Cancer Center member. He, his wife Kathleen Tai and their young children Myles and Raeya moved from Somerville, Massachusetts, where Westcott had been a postdoctoral fellow at the Koch Institute of Integrative Cancer Research at the Massachusetts Institute of Technology.

Westcott will take the passion and scientific hunger he developed and honed to the famed lab, where he plans to continue studies on colon cancer and the immune system.

“A lot of things attracted me to Cold Spring Harbor Laboratory,” said Westcott who had been to the lab during conferences, joining three Mechanisms and Models of Cancer meetings, and appreciated that the small size of the lab encourages collaboration and the sharing of ideas across disparate fields.

At this point, Westcott, who purchased a home in Dix Hills and started on campus on September 1st, has two technicians, Zakeria Aminzada and Colin McLaughlin working with him. He will be taking on a graduate rotation student from Stony Brook University soon and would also like to add a postdoctoral researcher within about six months. He plans to post ads for that position soon. 

Research directions

Westcott said his research has two major research directions.

The first, which is more translatable, involves looking at how T cells, which he described as the “major soldiers” of the immune system, become dysfunctional in cancer. These T cells balance between attacking unwanted and unwelcome cells relentlessly, disabling and destroying them, and ignoring cells that the body considers part of its own healthy system. When the T cells are too active, people develop autoimmunity. When they aren’t active enough, people can get cancer.

“Most cancers, particularly the aggressive and metastatic ones, have disabled the immune response in one way or another, and it is our focus to understand how so we can intervene and reawaken or reinvigorate it,” he explained.

During cancer development, T cells may recognize that something on a tumor is not healthy or normal, but they sometimes don’t attack. Depending on the type of genetic program within the T cells that makes them tolerant and dysfunctional, Westcott thinks he can reverse that.

A big push in the field right now is to understand what the genetic programs are that underlie different flavors of dysfunction and what cell surface receptors researchers can use as markers to define T cells that would allow them to identify them in patients to guide treatment.

Westcott is taking approaches to ablate or remove genes called nrf4a 1, 2 and 3. He is attacking these genes individually and collectively to determine what role they play in reducing the effectiveness of the body’s immune response to cancer.

“If we knock [some of these genes] out in T cells, we get a better response and tumors grow more poorly,” he said.

Westcott is exploring whether he can remove these genes in an existing T cell response to cause a regression of tumor development. He may also couple this effort with other immunotherapies, such as vaccines and agonistic anti-CD40 antibody treatment.

As a second research direction, Westcott is also looking more broadly at how tumors evolve through critical transitions. Taking an evolutionary biology perspective, he hopes to understand how the tumors start out as more benign adenoma, then become malignant adenocarcinoma and then develop into metastatic cancer. He is focusing in particular on the patterns of mutations and potential neoantigens they give rise to across the genome, while concentrating on the immune response against these neoantigens.

Each tumor cell is competing with tumor cells with other mutations, as well as with normal cells. “When they acquire new mutations that convey a selective advantage” those cells dominate and drive the growth of a tumor that can spread to the rest of the body, Westcott said.

Using a mouse model, he can study tumors with various mutations and track their T cell response.

T cells tend to be more effective in combating tumors with a high degree of mutations. These more mutated tumors are also more responsive to immunotherapy. Westcott plans to study events that select for specific clones and that might shift the prevalence, or architecture, of a tumor.

Some of the work Westcott has done has shown that it is not enough to have numerous mutations. It is also important to know what fraction of the cancer cells contain these mutations. For neoantigens that occur in only a small fraction of the total cells in the tumor, the T cell responses aren’t as effective and checkpoint blockade therapy doesn’t work.

He wants to understand how the T cell responses against these neoantigens change when they go from being subclonal “to being present in most or all of the tumor cells,” he explained. That can occur when a single or few tumor cells acquire a selective advantage. His hypothesis is that these selective events in tumor progression is inherently immunogenic. \

By exploring the fundamental architecture of a tumor, Westcott hopes to learn the mechanisms the tumor uses to evade the immune system.

Ocean breeze

As Westcott settles in at CSHL, he is excited by the overlap between what he sees around the lab and the Maine environment in which he was raised.

“Looking out the window to the harbor feels like New England and Maine,” he said. “It’s really nostalgic for me. Being near the ocean breeze is where I feel my heart is.”

Before his father shared the “Human Genome” book with him, Westcott was interested in rocks and frogs. In high school, his AP biology teacher helped drive his interest in the subject by encouraging discussions and participation without requiring her students to repeat memorized facts. The discussions “brought to life” the subject, he said.

As for his work, Westcott chose to study colon cancer because of its prevalence in the population. He also believes colon cancer could be a model disease to study all cancers. By understanding what differentiates the 12 percent of cases that are responses to immunotherapy from the remainder that don’t respond as well to such approaches, he hopes to apply these lessons to all cancer.

“There is a huge, unmet need,” he said.

Pixabay photo
Different dietary approaches may help modulate the immune system

By Dr. David Dunaief

Dr. David Dunaief

Autoimmune disease is when the body’s immune system attacks the organs, cells and tissues and causes chronic inflammation. However, this umbrella term refers to more than 80 different diseases (1). Some are familiar names, like type 1 diabetes, lupus, rheumatoid arthritis (RA), psoriasis, multiple sclerosis, and inflammatory bowel disease. Others, like Lambert-Eaton myasthenic syndrome and Cogan syndrome, are less well-known.

Chronic inflammation is the main consequence of immune system dysfunction, and it is the underlying theme tying these diseases together. Unfortunately, autoimmune diseases tend to cluster (2). Once you have one, you are at high risk for acquiring others. They disproportionately affect women, although men are also at risk.

Treating autoimmune diseases with meds

The primary treatment is immunosuppressives. In RA, for example, where there is swelling of joints bilaterally, a typical drug regimen includes methotrexate and TNF (tumor necrosis factor) alpha inhibitors, like Remicade (infliximab). These therapies seem to reduce underlying inflammation by suppressing the immune system and interfering with inflammatory factors, such as TNF-alpha. Disease-modifying anti-rheumatic drugs (DMARDs), a class that also includes Plaquenil (hydroxychloroquine), may slow or stop the progression of joint destruction and increase physical functioning.

However, there are several concerning factors with these drugs. First, the side-effect profiles are substantial. They includes risks of cancers, opportunistic infections and even death, according to black box warnings (the strongest warning required by the FDA) (3). Opportunistic infections include diseases like tuberculosis and invasive fungal infections.

It is no surprise that suppressing the immune system would increase the likelihood of infections. Nor is it surprising that cancer rates would increase, since the immune system helps to fend off malignancies. In fact, a study showed that after 10 years of therapy, the risk of cancer increased by approximately fourfold with the use of immunosuppressives (4).

Second, these drugs were tested and approved using short-term clinical trials; however, many patients are prescribed these therapies for 20 or more years.

So, what other methods are available to treat autoimmune diseases? Medical nutrition therapy using bioactive compounds and supplementation are being studied. Medical nutrition therapy may have immunomodulatory (immune system regulation) effects on inflammatory factors and on gene expression.

Managing inflammation with nutrition

Raising the level of beta-cryptoxanthin, a carotenoid bioactive food component, by a modest amount has a substantial impact in preventing RA. Several studies have also tested dietary interventions in RA treatment (5). Included were fasting followed by a vegetarian diet; a vegan diet; and a Mediterranean diet, among others. All mentioned here showed decreases in inflammatory markers, including c-reactive protein (CRP), and improvements in joint pain and other quality of life concerns.

Fish oil’s effects

Fish oil helps your immune system by reducing inflammation and improving your blood chemistry, affecting as many as 1,040 genes (6). In a randomized clinical study, 1.8 grams of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation had anti-inflammatory effects, suppressing cell signals and transcription factors (proteins involved with gene expression) that are pro-inflammatory.

In RA patients, fish oil helps suppress cartilage degradative enzymes, while also having an anti-inflammatory effect (7). A typical recommendation is to consume about 2 grams of EPA plus DHA to help regulate the immune system. Don’t take these high doses of fish oil without consulting your doctor, since fish oil may have blood-thinning effects.

Probiotic supplements

Approximately 70 percent of your immune system lives in your gut. Probiotics, by populating the gut with live beneficial microorganisms, have immune-modulating effects that decrease inflammation and thus are appropriate for autoimmune diseases. Lactobacillus salvirus and Bifidobacterium longum infantis are two strains that were shown to have positive effects (8, 9).

In a study with Crohn’s disease patients, L. casei and L. bulgaricus reduced the inflammatory factor TNF-alpha (10). To provide balance, I recommend probiotics with Lactobacillus to my patients, especially with autoimmune diseases that affect the intestines, like Crohn’s and ulcerative colitis.

Increasing fiber intake

Fiber has been shown to modulate inflammation by reducing biomarkers, such as CRP. In two separate clinical trials, fiber either reduced or prevented high CRP in patients. In one, a randomized clinical trial, 30 grams, or about 1 ounce, of fiber daily from either dietary sources or supplements reduced CRP significantly compared to placebo (11).

In the second trial, which was observational, participants who consumed the highest amount of dietary fiber (greater than 19.5 grams) had reductions in a vast number of inflammatory factors, including CRP, interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-alpha (12).

Immune system regulation is complex and involves over 1,000 genes, as well as many biomarkers. Dysfunction results in inflammation and, potentially, autoimmune disease. We know the immune system is highly influenced by bioactive compounds found in high-nutrient foods and supplements. Therefore, bioactive compounds may work in tandem with medications and/or may provide the ability to reset the immune system through immunomodulatory effects, treating and preventing autoimmune diseases.

References: 

(1) niaid.nih.gov. (2) J Autoimmun. 2007;29(1):1. (3) epocrates.com. (4) J Rheumatol 1999;26(8):1705-1714. (5) Front Nutr. 2017; 4: 52. (6) Am J Clin Nutr. 2009 Aug;90(2):415-424. (7) Drugs. 2003;63(9):845-853. (8) Gut. 2003 Jul;52(7):975-980. (9) Antonie Van Leeuwenhoek 1999 Jul-Nov;76(1-4):279-292. (10) Gut. 2002;51(5):659. (11) Arch Intern Med. 2007;167(5):502-506. (12) Nutr Metab (Lond). 2010 May 13;7:42.

Dr. David Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com.

Eating a high-fiber breakfast cereal is a great way to start. METRO photo
Increasing fiber intake may help modulate the immune system

By David Dunaief, M.D.

Dr. David Dunaief

When the immune system attacks the body’s own organs, cells and tissues and causes chronic inflammation, we classify it as an autoimmune disease. However, this umbrella term refers to more than 80 different diseases (1). Some are familiar names, like type 1 diabetes, lupus, rheumatoid arthritis (RA), psoriasis, multiple sclerosis, and inflammatory bowel disease. Others, like Lambert-Eaton myasthenic syndrome and Cogan syndrome, are less well-known.

Chronic inflammation is the main consequence of immune system dysfunction, and it is the underlying theme tying these diseases together. Unfortunately, autoimmune diseases tend to cluster (2). Once you have one, you are at high risk for acquiring others. Autoimmune diseases disproportionately affect women, although men do also get them.

Drug treatments

The mainstay treatment is immunosuppressives. In RA, for example, where there is swelling of joints bilaterally, a typical drug regimen includes methotrexate and TNF (tumor necrosis factor) alpha inhibitors, like Remicade (infliximab). These therapies seem to reduce underlying inflammation by suppressing the immune system and interfering with inflammatory factors, such as TNF-alpha. Disease-modifying anti-rheumatic drugs (DMARDs), a class that also includes Plaquenil (hydroxychloroquine), may slow or stop the progression of joint destruction and increase physical functioning.

However, there are several concerning factors with these drugs. First, the side-effect profile is substantial. It includes the risk of cancers, opportunistic infections and even death, according to black box warnings (the strongest warning required by the FDA) (3). Opportunistic infections include diseases like tuberculosis and invasive fungal infections.

It is no surprise that suppressing the immune system would result in increased infection rates. Nor is it surprising that cancer rates would increase, since the immune system helps to fend off malignancies. In fact, a study showed that after 10 years of therapy, the risk of cancer increased by approximately fourfold with the use of immunosuppressives (4).

Second, these drugs were tested and approved using short-term clinical trials; however, many patients are prescribed these therapies for 20 or more years.

So, what other methods are available to treat autoimmune diseases? Medical nutrition therapy using bioactive compounds, which have immunomodulatory (immune system regulation) effects on inflammatory factors and on gene expression, and supplementation are being studied.

Nutrition and inflammation

Raising the level of beta-cryptoxanthin, a carotenoid bioactive food component, by a modest amount has a substantial impact in preventing RA. Several studies have also tested dietary interventions in RA treatment (5). Included were fasting followed by a vegetarian diet; a vegan diet; and a Mediterranean diet, among others. All mentioned here showed decreases in inflammatory markers, including CRP, and improvements in joint pain and other quality of life concerns.

Fish oil supplementation

Fish oil helps your immune system by reducing inflammation and improving your blood chemistry, affecting as many as 1,040 genes (6). In a randomized clinical study, 1.8 grams of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation had anti-inflammatory effects, suppressing cell signals and transcription factors (proteins involved with gene expression) that are pro-inflammatory, such as NFkB.

In RA patients, fish oil helps suppress cartilage degradative enzymes, while also having an anti-inflammatory effect (7). When treating patients with autoimmune disease, I typically suggest about 2 grams of EPA plus DHA to help regulate their immune systems. Don’t take these high doses of fish oil without consulting your doctor, since fish oil may have blood-thinning effects.

Probiotic supplements

The gut contains approximately 70 percent of your immune system. Probiotics, by populating the gut with live beneficial microorganisms, have immune-modulating effects that decrease inflammation and thus are appropriate for autoimmune diseases. Lactobacillus salvirus and Bifidobacterium longum infantis are two strains that were shown to have positive effects (8, 9).

In a study with Crohn’s disease patients, L. casei and L. bulgaricus reduced the inflammatory factor TNF-alpha (10). To provide balance, I recommend probiotics with Lactobacillus to my patients, especially with autoimmune diseases that affect the intestines, like Crohn’s and ulcerative colitis.

Fiber intake

Fiber has been shown to modulate inflammation by reducing biomarkers, such as CRP. In two separate clinical trials, fiber either reduced or prevented high CRP in patients. In one, a randomized clinical trial, 30 grams, or about 1 ounce, of fiber daily from either dietary sources or supplements reduced CRP significantly compared to placebo (11). In the second trial, which was observational, participants who consumed the highest amount of dietary fiber (greater than 19.5 grams) had reductions in a vast number of inflammatory factors, including CRP, interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-alpha (12).

Immune system regulation is complex and involves over 1,000 genes, as well as many biomarkers. Dysfunction results in inflammation and, potentially, autoimmune disease. We know the immune system is highly influenced by bioactive compounds found in high nutrient foods and supplements. Therefore, bioactive compounds may work in tandem with medications and/or may provide the ability to reset the immune system through immunomodulatory effects and thus treat and prevent autoimmune diseases.

References:

(1) niaid.nih.gov. (2) J Autoimmun. 2007;29(1):1. (3) epocrates.com. (4) J Rheumatol 1999;26(8):1705-1714. (5) Front Nutr. 2017; 4: 52. (6) Am J Clin Nutr. 2009 Aug;90(2):415-424. (7) Drugs. 2003;63(9):845-853. (8) Gut. 2003 Jul;52(7):975-980. (9) Antonie Van Leeuwenhoek 1999 Jul-Nov;76(1-4):279-292. (10) Gut. 2002;51(5):659. (11) Arch Intern Med. 2007;167(5):502-506. (12) Nutr Metab (Lond). 2010 May 13;7:42.

Dr. David Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com. 

By David Dunaief, M.D.

Autoimmune diseases are becoming increasingly common, affecting approximately 23.5 million Americans, with 78 percent of them women. These numbers are expected to continue rising. There are more than 80 conditions with autoimmunity implications (1). These diseases include rheumatoid arthritis (RA), lupus, thyroid (hypo and hyper), psoriasis, multiple sclerosis and inflammatory bowel disease, to mention just a few.

Dr. David Dunaief

Autoimmune diseases are defined by the immune system inappropriately attacking organs, cells and tissues of the body, causing chronic inflammation. Thus, inflammation is the main consequence of immune system dysfunction, and it is the underlying theme tying these diseases together. Unfortunately, autoimmune diseases tend to cluster (2). In other words, once you have one, you are much more likely to acquire others.

Drug treatments

The mainstay of treatment is immunosuppressives. For example, in RA where there is swelling of joints bilaterally, the typical drug regimen includes methotrexate and TNF (tumor necrosis factor) alpha inhibitors, like Remicade (infliximab). These therapies are thought to help reduce the underlying inflammation by suppressing the immune system and interfering with inflammatory factors, such as TNF-alpha. The disease-modifying antirheumatic drugs (DMARDs) may slow or stop the progression of joint destruction and increase physical functioning. Remicade reduces C-reactive protein (CRP), a biomarker of inflammation.

However, there are several concerning factors with these drugs. First, the side effect profile is substantial. It includes the risk of cancers, opportunistic infections and even death, according to black box warnings (the strongest warning by the FDA) (3). Opportunistic infections include diseases like tuberculosis and invasive fungal infections. It is no surprise that suppressing the immune system would result in increased infection rates. Nor is it surprising that cancer rates would increase, since the immune system helps to fend off malignancies. In fact, a study showed that after 10 years of therapy, the risk of cancer increased by approximately fourfold with the use of immunosuppressives (4).

Second, these drugs were tested and approved using short-term randomized clinical trials, but many patients are put on these therapies for 20 or more years. Remicade’s package insert was approved with approximately two years of data.

So what other methods are available to treat autoimmune diseases? These include medical nutrition therapy using bioactive compounds, which have immunomodulatory (regulation of the immune system) effects on inflammatory factors and on gene expression, and supplementation.

Nutrition and inflammation

Raising the level of beta-cryptoxanthin, a carotenoid bioactive food component, by a modest amount has a substantial impact in preventing RA. In one study, participants drank the equivalent of about one glass of freshly squeezed orange juice a day with a resultant 49 percent risk reduction in the development of RA (5).

While I have not found studies that specifically tested diet in RA treatment, there are dietary studies that have shown anti-inflammatory effects in other diseases, using biomarkers such as CRP and TNF-alpha. In a study that looked at the Mediterranean-type diet in 112 older patients, there was a significant decrease in inflammatory markers, including CRP (6).

In another study, participants showed a substantial reduction in CRP with increased flavonoid levels, an antioxidant, from vegetables and apples. Astaxanthin, a carotenoid found in fish, was shown to significantly reduce a host of inflammatory factors in mice, including TNF-alpha (7).

Vitamin D

Vitamin D is ubiquitous in helping to treat and prevent many chronic diseases — autoimmune diseases are no exception. Vitamin D affects over 200 genes, according to Wellcome Trust Centre for Human Genetics at University of Oxford. In the absence of vitamin D, T-cell response, part of the immune system, becomes dysfunctional and uncontrollable, resulting in an increase in multiple sclerosis (MS) and inflammatory bowel disease — Crohn’s and ulcerative colitis. However, when normal levels of vitamin D are conveyed to the vitamin D receptors, proper T-cell functioning is restored with no subsequent autoimmune disease, at least in animal studies (8).

Interestingly, multiple sclerosis patients are notoriously very low in vitamin D, and it is difficult to raise the levels. There was a small study proclaiming that MS patients may need as much as 50,000 IUs of vitamin D2 weekly, and that it was safe (9). I would check with a neurologist specializing in MS before taking such a high dose.

Fish oil

Fish oil helps your immune system by reducing inflammation and improving your blood chemistry.

If you think vitamin D is impressive, fish oil affects as many as 1,040 genes (10). In a randomized clinical study, 1.8 grams of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation had anti-inflammatory affects, suppressing cell signals and transcription factors (proteins involved with gene expression) that are pro-inflammatory, such as NFkB.

In RA patients, fish oil helps suppress cartilage degradative enzymes, while also having an anti-inflammatory effect (11). When treating patients with autoimmune disease, I typically suggest about 2 grams of EPA plus DHA to help regulate their immune systems. Don’t take these high doses of fish oil without consulting your doctor, since fish oil may have blood thinning effects.

Probiotic supplements

The gut contains approximately 70 percent of your immune system. Probiotics, by populating the gut with live beneficial microorganisms, have immune-modulating effects that decrease inflammation and thus are appropriate for autoimmune diseases. Lactobacillus salvirus and Bifidobacterium longum infantis are two strains that were shown to have positive effects (12, 13).

In a study with Crohn’s disease patients, Lactobacillus casei and L. bulgaricus reduced the inflammatory factor, TNF-alpha (14). To provide balance, I recommend probiotics with Lactobacillus to my patients, especially with autoimmune diseases that affect the intestines, like Crohn’s and ulcerative colitis.

Fiber

Fiber has been shown to modulate inflammation by reducing biomarkers, such as CRP. In two separate clinical trials, fiber either reduced or prevented high CRP in patients. In one, a randomized clinical trial, 30 grams, or about 1 ounce, of fiber daily from either dietary sources or supplements reduced CRP significantly compared to placebo (15).

In the second trial, which was observational, participants who consumed the highest amount of dietary fiber (greater than 19.5 grams) had reductions in a vast number of inflammatory factors, including CRP, interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-alpha. (16).

Immune system regulation is complex and involves over a 1,000 genes, as well as many biomarkers. Dysfunction results in inflammation, and potentially autoimmune disease. We know the immune system is highly influenced by bioactive compounds found in high nutrient foods and supplements. Therefore, bioactive compounds may work in tandem with medications and/or may provide the ability to reset the immune system through immunomodulatory effects and thus treat and prevent autoimmune diseases.

References: (1) niaid.nih.gov. (2) J Autoimmun. 2007;29(1):1. (3) epocrates.com. (4) J Rheumatol 1999;26(8):1705-1714. (5) Am J Clin Nutr. 2005 Aug; 82(2):451-455. (6) Am J Clin Nutr. 2009 Jan;89(1):248-256. (7) Chem Biol Interact. 2011 May 20. (8) Prog Biophys Mol Biol. 2006 Sept;92(1):60-64. (9) Am J Clin Nutr. 2007 Sep;86(3):645-651. (10) Am J Clin Nutr. 2009 Aug;90(2):415-424. (11) Drugs. 2003;63(9):845-853. (12) Gut. 2003 Jul;52(7):975-980. (13) Antonie Van Leeuwenhoek 1999 Jul-Nov;76(1-4):279-292. (14) Gut. 2002;51(5):659. (15) Arch Intern Med. 2007;167(5):502-506. (16) Nutr Metab (Lond). 2010 May 13;7:42.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management.