There are hundreds of investigators in the HSCI network solving different problems related to cell biology and illness. This month, we feature recently published work by three laboratories on: a therapy for graft-versus-host disease, intestinal stem cell circadian rhythms, and new hope for people suffering from a rare blood disorder.
Human Clinical Trials Move Forward With Promising Therapy for Graft-Verses-Host Disease
HSCI investigators have developed a better picture of why a recently discovered therapy for graft-versus-host disease (GVHD) is more effective than anything currently available to patients.
In 2011, human clinical trials showed that immune system signaling molecule interleukin 2 (IL-2) both improved GVHD symptoms in patients and completely stopped the progression of the condition. Surprisingly, HSCI Executive Committee member Jerome Ritz, MD, and his team at the Dana-Farber Cancer Institute found that patients who received a continuous low dose of IL-2, which is an FDA-approved drug that stimulates immune cells to attack certain types of cancers, saw reduced GVHD symptoms because their immune response was suppressed. "It's interesting because it changes the paradigm," Ritz said. "You think something stimulates the immune system, but actually what it does is the opposite."
Bone marrow transplants are life-saving treatments for patients with leukemia and lymphoma that completely replace a recipient's faulty blood-forming stem cells with those of a matching donor. Despite immunologic differences between the donor and recipient, the donor immune system often recognizes that it is in a new place and adapts. When recognition does not happen, the donor's immune system begins to attack the recipient's tissues, causing the uncomfortable and difficult-to-manage symptoms of GVHD.
Ritz's team found that IL-2 affects the relationship between the immune cells that mount the body's immune response (effector T cells) and the immune cells that maintain the body's ability to differentiate between self and non-self tissue (regulatory T cells). The researchers observed that patients with GVHD have a lower level of regulatory T cells and higher level of effector T cells than normal. Low doses of IL-2 can increase the presence of regulatory T cells sevenfold and help them survive longer. The growing population of regulatory T cells then competes for IL-2 with effector T cells, preventing them from getting switched on.
"The immune system functions in checks and balances," Ritz said. "We found that not only was their relatively less IL-2 in GVHD patients, but there was relative more other cytokines, IL-7 and IL-15, that primarily supported effector T cells and didn't support regulatory T cells." Ritz's work is inspiring multi-center studies looking at how IL-2 can work in other immune diseases, and whether early use of IL-2 can reduce tissue damage caused by GVHD.
Ritz's research partners included John Koreth, MBBS, DPhil, Ken-ichi Matsuoka, MD, PhD, and Haesook Kim, PhD, also of Dana-Farber Cancer Institute.
Source: Low-Dose Interluekin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease. Science Translational Medicine. April 3, 2013.
Image: Interleukin 2 [Emw/wikimedia commons] Caption: The molecular structure of Interleukin 2.
Research on Fruit Fly Intestines Shows Stem Cell Regeneration Follows a Circadian Rhythm
Like humans, fruit flies the sun shines. They wake at dawn, eat what they can find, and sleep at dusk. This twenty-four-hour routine, called a circadian rhythm, is controlled by the sun's light-dark cycle. The clock is set so a fly, or human, is primed to be active during the day and inactive at night.
Circadian rhythms may also be involved in stem cell replication, according to a surprising discovery by Phillip Karpowicz, PhD, a Harvard Medical School research fellow in genetics. While studying stem cell replication in fruit fly intestines, he found the circadian rhythm gene period to be a necessary factor in regulating this activity. "I was shocked when the circadian clock genes were hits in my screen," he said. "I didn't think that regeneration would follow any particular timing."
Experiments showed flies that express the period gene have a predictable, synchronous replication of their intestinal stem cells that follows a twenty-four-hour cycle. The timing of the cell division matches with the timing of when flies eat their meals. Flies that had their period gene expression blocked experienced an asynchronous or poor intestinal stem cell division.
Karpowicz believes that his finding has implications for identifying the best times for cancer therapies to be administered in humans "I think certain interventions, like chemotherapy and radiation therapy that can kill dividing cells in the intestinal lining need to take timing into account," he said. Karpowicz will next be looking in mice to see if circadian rhythm genes are involved in mammalian intestinal regeneration.
Karpowicz works in the lab of Harvard Stem Cell Institute Affiliated Faculty member Norbert Perrimon, PhD, the James Stillman Professor of Developmental Biology in the Harvard Medical School Department of Genetics.
Source: The Circadian Clock Gates the Intestinal Stem Cell Regenerative State. Cell Reports. April 25, 2013.
Image: Fly with clock over its gut [Credit: Young Kwan]. Caption: The circadian clock controls intestinal stem cell regeneration in fruit flies.
Healthy Stem Cells Generated From Terminally Ill Patients with Pearson Marrow Pancreatic Syndrome
Using a difficult laboratory technique, HSCI physicain-researchers have isolated genetically healthy stem cells from patients with Pearson Marrow Pancreas Syndrome (PS), a generally fatal infant blood disorder with less than a hundred reported cases worldwide. Children with PS experience a range of symptoms, most notably: anemia, decreased organ function, and difficulty absorbing nutrients and gaining weight. Blood transfusions can prolong life, but once diagnosed, a PS patient isn't expected to make it past his or her fifth birthday.
HSCI Principal Faculty member Suneet Agarwal, MD, PhD, at Boston Children's Hospital, is one of only a few physicians in the United States actively researching rare blood disorders like PS. "At Children's, I get exposed to these diseases because of our referrals from around the country and around the world to care for these patients," he said.
Pearson Marrow Pancreas Syndrome is caused by a deletion of a specific region of a person's mitochondrial DNA. In addition to a complete set of parental chromosomes, all human cells carry additional genes in their mitochondria, mostly dedicated to energy production. In PS, varying levels of mutant mitochondrial DNA in different cells determines the severity of symptoms for individuals with the disease, leading to a diagnosis with no sure prognosis.
Curious to learn more about PS at the molecular level, Agarwal's lab, in collaboration with HSCI Executive Committee member George Daley, MD, PhD, reprogrammed cells from patients into induced pluripotent stem cells. Despite technical challenges and due to the mixture of affected mitochondria found in patients, Agarwal was able to isolate stem cells that had no mutant mitochondrial DNA. "While making these manipulations, all of a sudden, in our hands is something genetically identical to the patient, a living cell, that doesn't have the defect anymore," he said, "so it essentially corrected itself."
With the support of a 2013 HSCI Seed Grant, Agarwal plans to investigate whether his technical achievement can translate into patient therapies.
Source: Induced Pluripotent Stem Cells with a Pathological Mitochondrial DNA Deletion. Stem Cells. February 12, 2013
Image: PS-Affected Cells [Credit: Suneet Agarwal] Caption: Mitochondrial DNA fluoresence in situ hybridization showing normal mitochondrial DNA in yellow and mutated mitochondrial DNA in green.
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The Harvard Stem Cell Institute is a collaborative of more than 1,000 leading scientists, postdoctoral fellows, graduate students, and undergraduate students who are affiliated with one or more of the University's schools and affiliated hospitals and medical institutions, and are working to advance the understanding and use of stem cells in basic research and regenerative medicine.
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