Written by: Rebecca Tweedell
Written By; Kaitlyn Sadtler
Original Article: Li et al. Journal of Immunology 2018
The Gist of It:
If you’ve watched ER or Grey’s Anatomy, you’ve probably heard of a patient “rejecting” their organ transplant. This happens when the patient’s body notices that the transplanted organ is not part of itself and starts to attack it because it is foreign. The part of our body that rejects a transplanted organ is our immune system, the same system that helps fight against infections like the flu. In certain kinds of transplants, like bone marrow transplants, immune cells are the “organ” transplanted into a patient, and sometimes things can go awry, leading to the transplanted immune cells attacking the patient because they see the whole patient’s body as foreign. This type of reaction is called graft versus host disease, or GVHD. This is caused by a type of inflammatory response that is similar to the response seen when fighting off an infection. Recently, researchers at the University of Iowa have discovered that the immune response to intestinal parasitic worms (which is different than the response during infections or GVHD) can actually decrease GVHD symptoms through a specific biologic pathway. The worm, Heligmosomoides polygyrus bakeri (we’ll just call it “worm”), makes the immune system secrete a certain protein called interleukin-4, or IL-4. This protein stimulates the growth of regulatory T cells – called Tregs. In general, Tregs help dampen the immune system and calm down inflammatory responses. In the case of having both a parasitic worm infection and GVHD from a bone marrow transplant, the worms stimulate these Tregs to calm down the inflammatory response of GVHD through a different protein called TGF-β. These studies could help us understand how to naturally decrease GVHD, a disease with minimal treatment options, and discover new therapies to help manage GVHD after bone marrow transplants.
(It is important to note that these proposed future therapies will require learning from our body’s response to parasitic worms, not the 1900’s-style order a tapeworm from a questionable source. If you know someone suffering from GVHD please consult a licensed physician for all treatments)
The Nitty Gritty:
Using a murine model of GVHD after bone marrow transplant with concurrent Heligmosomoides polygyrus bakeri infection, Li et al. showed that helminthic infection can reduce the symptoms of GVHD through induction of TGF-β and Treg expansion via IL-4 signaling that is dependent upon GATA3 activity. Though previous studies indicated invariable natural killer T cells (iNKTs) were a critical mediator of IL-4–dependent Treg induction by helminths, this study showed that in Ja8-/- mice, which lack iNKTs, helminth-induced Treg expansion was maintained, suggesting that a multitude of cells produce IL-4. Interestingly, production of TGF-β and expansion of Tregs were reliant upon the GATA3 transcription factor. These results could be used to identify new therapies; the current standard of care is immunosuppressive drugs, which can be minimally effective in GVHD and come with adverse side effects.
Original Research Article: Li, Yue, et al. “Helminth-Induced Production of TGF-β and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells.” The Journal of Immunology 201.10 (2018): 2910-2922.
Written by: Padmini S. Pillai
Original Article: Caldwell et al, eLIFE 2018
The Gist of It:
Many of you may remember Taz, the beloved Tasmanian devil from The Looney Tunes Show, known for his voracious appetite and short temper. The real-life carnivorous marsupials that inspired this cartoon character are currently on the verge of extinction due to the rapid spread of a contagious cancer called Devil Facial Tumor Disease (DFTD). Recently, two different transmittable cancers have emerged in the devils, DFT1 in 1996 and DFT2 in 2014; these have resulted in the death of nearly 80% of the devil population. Tasmanian devils transmit the cancer through biting and then die from starvation as tumors grow uncontrollably on their face and mouth. Normally, cancers are not contagious because the immune system is able to distinguish foreign (non-self) cells from cells that belong within the body, using a molecule called major histocompatibility complex class I (MHC-I). T cells in the immune system recognize non-self MHC-I molecules on cells that don’t belong and destroy them. The process of identifying non-self MHC-I can protect us from bacteria and viruses, but it can also lead to organ transplant rejection. DFT1 cancer cells escape recognition by the Tasmanian devil immune system by simply not expressing MHC-I molecules on their surface. Without the non-self MHC-I, the body can’t identify that the cancer cells don’t belong. Until recently, it wasn’t clear whether the same was true for DFT2. A paper by Caldwell and colleagues used cells collected from tumors and cancer cells grown in the lab to explain how DFT2 spreads. Unlike DFT1, DFT2 cells still have MHC-I on their surface, but they express an MHC-I molecule that is genetically similar to those expressed in most Tasmanian devils. This allows the cancer cells to spread through the devil population without any T cells recognizing them as foreign. To make matters worse, analyses of tumors from many Tasmanian devils show that some DFT2 cancers are also beginning to lose their MHC-I, just like DFT1! This study gives us a close look at how contagious cancers can evolve rapidly, especially in endangered populations. Further research on how contagious cancers avoid recognition by our immune system could not only help save the Tasmanian devils, but could potentially shed light on ways to prevent transplant rejection.
The Nitty Gritty:
DFT2 cells were grown in culture and analyzed by flow cytometry to demonstrate expression of beta-2 microglobulin (β2M), a component of the MHC-I molecule. Quantification by RT-qPCR revealed that DFT2 cells expressed both classical and non-classical MHC-I heavy chain genes. Antibodies against classical and non-classical MHC-I heavy chains were generated and used to analyze expression of MHC-I in sections from primary DFT2 tumors. Staining revealed that surface expression of MHC-I in tumors is quite variable. Staining for CD3+ cells revealed that lymphocytic infiltration does occur in DFT2 tumors. Different DFT2 clones were found to express each of the five devil genomic MHC-I sequences, including some expressed by interferon gamma-simulated DFT1 tumor cells. Additionally, analysis of splenic mRNA samples from infected devils showed sequence similarity between MHC-I alleles expressed in three different hosts.
Original Research Article: Caldwell, Alison, et al. “The newly-arisen Devil facial tumour disease 2 (DFT2) reveals a mechanism for the emergence of a contagious cancer.” eLIFE 14;7 (2018): pii: e35314
Written By: Ritu Raman
Original Article: Osaki et al. Science Advances 2018
The Gist of It:
Treating a disease requires understanding it: What goes wrong? When does it go wrong? Does it get worse with time? With amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease, the cause of gradually and progressive death of the motor neurons (brain cells) that control skeletal muscle is generally unknown and, thus far, unsolved. A new way that scientists are trying to understand the onset and progression of diseases is through “organ-on-a-chip” technology. This is exactly what it sounds like – small volumes of engineered living tissues are grown inside a polymer device called a microfluidic chip. To study a disease like ALS requires an ALS-on-a-chip device that contains two types of tissues: motor neurons and skeletal muscle. In this paper, Osaki et al. develop an ALS-on-a-chip device using cells from a patient with sporadic ALS. They cultured neurons in one compartment of the device and muscle in another, and allowed them to form connections called “neuromuscular junctions” similar to how these tissues are connected in our bodies. In our bodies, when neurons are stimulated, the signal travels down through the neuromuscular junction to make the muscle contract. This group of scientists showed that, compared to healthy neurons, ALS neurons degrade and generate fewer contractions in the muscle. They were then able to test a few different drugs on their chip and showed that treatment with the drugs rapamycin and bosutinib in parallel could potentially help treat ALS. The platform Osaki et al. have developed allows us to study a debilitating and deadly disease and help test potential treatments in the lab before testing them in humans. This makes it more likely that a clinical trial conducted with these treatments will be effective. ALS-on-a-chip is one of many organ-on-a-chip systems being developed by engineers and scientists, and this technology could help us understand and treat many diseases that affect our lives and communities.
The Nitty Gritty
Osaki et al. manufactured microfluidic devices using poly (dimethylsiloxane) (PDMS). Within each device were distinct spatial regions for neurons and muscle, with a region in between for the formation of neuromuscular junctions. Both cell types were derived from human induced pluripotent stem cells (iPSCs). The ALS cells were harvested from a patient with sporadic ALS, and all neurons were genetically engineered to incorporate the light-sensitive ion channel, channelrhodopsin-2, ensuring that the neurons could be externally stimulated using blue light. Neurons and muscle cells were seeded separately and cultured until neurites extended to form neuromuscular junctions with muscle fiber bundles. Light stimulation of neurons was used to drive muscle contraction, and the force of muscle contraction was measured by tracking the deflection of flexible micro-pillars to which the muscle was attached inside the device. Immunostaining and fluorescent imaging of the tissue was used to confirm the spatial patterning and integration of the two cell types. The team then tested the effect of rapamycin and bosutinib on the morphology, viability, and functionality of the ALS-on-a-chip unit, demonstrating that this platform could be used to both understand disease progression and conduct high-throughput screening of therapeutic drugs with potential to treat ALS.
Original Research Article: Osaki, T., Uzel, S.G. and Kamm, R.D., 2018. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Science advances, 4(10), p.eaat5847.
Written By: Kathleen Cunningham