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Expanding A Lymph Node, Boosting A Vaccine

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This immunofluorescent staining shows a lymph node that has been significantly expanded in mice with the help of the biomaterial MPS-vaccine (on the right), next to a lymph node taken from non-treated control mice (on the left) at the same time post-vaccination. 

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Credit: Wyss Institute at Harvard University

Expanding a lymph node, boosting a vaccine

A biomaterial vaccine enhances and sustains lymph node expansion following vaccination, boosting anti-tumor immunity in an animal model.

By Benjamin Boettner

(BOSTON) — Each one of us has around 600 lymph nodes (LNs) – small, bean-shaped organs that house various types of blood cells and filter lymph fluid – scattered throughout our bodies. Many of us have also experienced some of our LNs to temporarily swelling during infections with viruses or other pathogens. This LN expansion and subsequent contraction can also result from vaccines injected nearby, and in fact is thought to reflect the ongoing vaccine immune response. While researchers have studied the early expansion of LNs following vaccination, they have not investigated whether prolonged LN expansion could affect vaccine outcomes.

Now, for the first time, researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and Genentech, a member of the Roche Group found a way to enhance and extend LN expansion, and study how this phenomenon affects both the immune system and efficacy of vaccinations against tumors. Key to their approach was a biomaterial vaccine formulation that enabled greater and more persistent LN expansion than standard control vaccines. While the oversized LNs maintained a normal tissue organization, they displayed altered mechanical features and hosted higher numbers of various immune cell types that commonly are involved in immune responses against pathogens and cancers. Importantly, "jump-starting" lymph node expansion prior to administering a traditional vaccine against a melanoma-specific model antigen led to more effective and sustained anti-tumor responses in mice. The findings are published in Nature Biomedical Engineering. 

"By enhancing the initial and sustained expansion of LNs with biomaterial scaffolds, non-invasively monitoring them individually over long time periods, and probing deeply into their tissue architecture and immune cell populations, we tightly correlate a persistent LN expansion with more robust immune and vaccination responses," said Wyss Institute Founding Core Faculty member David Mooney, Ph.D., who led the study. "This opens a new front of investigation for immunologists, and could have far-reaching implications for future vaccine developments." Mooney also is the Robert P. Pinkas Family Professor of Bioengineering at SEAS, and a co-principal investigator of the NIH-funded and Wyss-coordinated Immuno-Engineering to Improve Immunotherapy (i3) Center.

Mooney's team at the Wyss Institute and SEAS had previously developed different biomaterial scaffolds as a matrix for cancer and infection vaccines. The researchers have demonstrated the potential of biomaterial vaccine formulations to successfully fight the growth of tumors in an extensive body of work performed in preclinical animal models and a first clinical trial with cancer patients. But they hadn't yet investigated how their vaccines and those developed by others could influence the response of LNs draining leaked tissue fluid at vaccine injection sites, and have an impact on the LNs tissue organization, different cell types, and their gene expression, which could in turn affect vaccine efficacy. In their new study, they tested a previously developed vaccine formulation that is based on microscale mesoporous silica (MPS) rods that can be injected close to tumors and form a cell-permeable 3D scaffold structure under the skin. Engineered to release an immune cell-attracting cytokine (GM-CSF), and immune cell-activating adjuvant (CpG), and tumor-antigen molecules, MPS-vaccines are able to reprogram recruited so-called antigen-presenting cells that, upon migrating into nearby LNs, orchestrate complex tumor cell-killing immune responses. Their new study showed that there are more facets to that concept.

"As it turns out, the immune-boosting functions of basic MPS-vaccines actively change the state of LNs by persistently enlarging their whole organ structure, as well as changing their tissue mechanics and immune cell populations and functions," said first-author Alexander Najibi, Ph.D., who performed his Ph.D. Thesis with Mooney.

Probing LNs with ultra-sound and nano-devices

To understand the response of LNs to MPS-vaccines over time, the team applied an ultra-sound imaging technique known as high-frequency ultrasound (HFUS). Similar to monitoring a tiny fetus developing in a mother's womb by clinical ultra-sound, HFUS, on a much smaller scale, enables non-invasively and non-destructively monitoring of anatomical details of tissues and organs in small animals such as mice. Using HFUS, the team traced individual LNs in MPS-vaccinated mice over 100 days. They identified an initial peak expansion period that lasted until day 20, in which LN volumes increased about 7-fold, significantly greater than in animals that received traditional vaccine formulations. Importantly, the LNs of MPS-vaccinated mice, while decreasing in volumes after this peak expansion, remained significantly more expanded than LNs from traditionally vaccinated mice throughout the 100-day time course.

When Najibi and the team investigated the mechanical responses of the LNs using a nanoindentation device, they found that LNs in MPS-vaccinated animals, although maintaining an overall normal structure, were less stiff and more viscous in certain locations. This was accompanied by a re-organization of a protein that assembles and controls cells' mechanically active cytoskeleton. Interestingly, Mooney's group had shown in an earlier biomaterial study that changing mechanical features of immune cells' environments, especially their viscoelasticity, affects immune cell development and functions. "It is very well-possible that in order to accommodate the significant growth induced by MPS-vaccines, LNs need to become softer and more viscous, and that this then further impacts immune cell recruitment, proliferation, and differentiation in a feed-forward process," said Najibi.

From immune cell engagement to vaccine responses

Interestingly, upon MPS-vaccination, the numbers of "innate immune cells," including monocytes, neutrophils, macrophages, and other cell types that build up the first wave of immune defenses against pathogens and unwanted cells, peaked first in expanding LNs. Peaking with a delay were dendritic cells (DCs), which normally transfer information in the form of antigens from invading pathogens and cancer cells to "adaptive immune cells" that then launch subsequent waves of highly specific immune responses against the antigen-producing invaders. In fact, along with DCs, also T and B cell types of the adaptive immune system started to reach their highest numbers. "It was fascinating to see how the distinct changes in immune cell populations that we detected in expanding LNs in response to the MPS-vaccine over time re-enacted a typical immune response to infectious pathogens," commented Najibi. 

Innate immune cells and DCs are also known as "myeloid cells," which are known to interact with LN tissue during early expansion. To further define the impact of myeloid cells on LN expansion, Mooney's team collaborated with the group of Shannon Turley, Ph.D., the VP of Immunology and Regenerative Medicine at Genentech, and an expert in lymph node biology and tumor immunology. "The MPS-vaccine led to extraordinary structural and cellular changes within the lymph node that supported potent antigen-specific immunity," said Turley.

By isolating myeloid cells from LNs and analyzing the gene expression profiles of individual cells (single cell RNA-seq), the groups were able to reconstruct distinct changes in myeloid cell populations during LN expansion, and identified distinct DC populations in durably expanded LNs whose changed gene expression was associated with LN expansion. In addition, the collaborators found that the number of monocytes was increased 80-fold upon MPS-vaccination – the highest increase among all myeloid cell types – and pinpointed subpopulations of "inflammatory and antigen-presenting monocytes" as promising candidates for facilitating LN expansion. In fact, when they depleted specific subpopulations of these types of monocytes from circulating blood of mice after vaccination, the maintenance of LN expansion, and timing of the T cell response to vaccination, was altered.

Finally, the team explored whether LN expansion could enhance the effectiveness of vaccination. "Jump-starting" the immune system in LNs with an antigen-free MPS-vaccine and subsequently administering the antigen in a traditional vaccine format significantly improved anti-tumor immunity and prolonged the survival of melanoma-bearing mice, compared to the traditional vaccine alone. "The priming of lymph nodes for subsequent vaccinations using various formulations could be a low-hanging fruit for future vaccine developments," said Mooney.

"This newfound ability to physically expand lymph nodes and enhance their various immune activities over longer treatment courses, using cleverly designed and easy-to-administer biomaterials, could provide a tremendous push to immunotherapies in patients. It is also yet another great example of how mechanics plays a key role in regulation of living systems, even immune responses where few would consider physical cues to be important," said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

Other authors on the study are Ryan Lane, Miguel Sobral, Giovanni Bovone, Shawn Kang, Benjamin Freedman, Joel Gutierrez Estupinan, Alberto Elosegui-Artola, Christina Tringides, Maxence Dellacherie, Katherine Williams, Hamza Ijaz, and Sören Müller. The study was funded by the National Institutes of Health/National Cancer Institute (award# U54 CA244726 and R01 CA223255).

PRESS CONTACT

Wyss Institute for Biologically Inspired Engineering at Harvard UniversityBenjamin Boettner, benjamin.Boettner@wyss.Harvard.Edu

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The Wyss Institute for Biologically Inspired Engineering at Harvard University (www.Wyss.Harvard.Edu) is a research and development engine for disruptive innovation

The Harvard John A. Paulson School of Engineering and Applied Sciences (http://seas.Harvard.Edu) serves as the connector and integrator of Harvard's teaching and research efforts in engineering, applied sciences, and technology. Through collaboration with researchers from all parts of Harvard, other universities, and corporate and foundational partners, we bring discovery and innovation directly to bear on improving human life and society.

 

Journal

Nature Biomedical Engineering

Method of Research

Experimental study

Subject of Research

Animals

Article Title

Durable lymph-node expansion is associated with the efficacy of therapeutic vaccination

Article Publication Date

6-May-2024

What To Expect From CLL Treatment

Photo Credit: iStock/Getty Images

SOURCES:

Texas Oncology: "Early-Stage Asymptomatic Chronic Lymphocytic Leukemia," "Symptomatic Advanced Chronic Lymphocytic Leukemia."

American Cancer Society: "Typical Treatment of Chronic Lymphocytic Leukemia," "Chemotherapy for Chronic Lymphocytic Leukemia," "Monoclonal Antibodies for Chronic Lymphocytic Leukemia," "Targeted Therapy for Chronic Lymphocytic Leukemia," "Immunotherapy for Non-Hodgkin Lymphoma," "Stem Cell Transplant for Chronic Lymphocytic Leukemia," "Supportive or Palliative Care for Chronic Lymphocytic Leukemia."

Targeted Oncology: "Current and Emerging Treatment Options in Chronic Lymphocytic Leukemia."

Blood: "Abbreviated Regimen with 4 Cycles of Fludarabine, Cyclophosphamide and Rituximab (FCR) in Physically Fit Patients with Chronic Lymphocytic Leukemia Who Achieve Early Complete Remission with Undetectable Minimal Residual Disease: Safety and Efficacy Follow-up Results of a Single Center Experience."

Macmillan Cancer Support (UK): "FCR Chemotherapy."

American Society of Clinical Oncologists' Cancer.Net: "Leukemia -- Chronic Lymphocytic -- CLL: Types of Treatment."

Leukemia & Lymphoma Society: "Chemotherapy and Drug Therapy."

Cancernetwork (online version of journal Oncology): "Ibrutinib Superior to Chemoimmunotherapy in Treatment-Naïve CLL," "Reasons for Ibrutinib Discontinuation Linked With Length of CLL Survival."

Canadian Cancer Society: "Tumor Lysis Syndrome," "Targeted Therapy for Chronic Lymphocytic Leukemia."

Cancer Research U.K.: "Steroids."

GetPalliativeCare.Org: "What Is Palliative Care?"

American Institute for Cancer Research: "Vegetarian and Vegan Diets," "Physical Activity and Cancer."

National Cancer Institute: "Eating Hints: Before, During, and After Cancer Treatment."

Leukemia Research: "Green tea polyphenol 'epigallocatechin-3-gallate', differentially induces apoptosis in CLL B-and T-Cells but not in healthy B-and T-Cells in a dose dependant manner."

Leukemia & Lymphoma: "Rapamycin and curcumin induce apoptosis in primary resting B chronic lymphocytic leukemia cells."

Dealing With Swollen Feet? Try These Natural Remedies For Relief

Are you experiencing swelling in your feet? Swollen feet, medically known as oedema, can be uncomfortable and inconvenient. It can be caused due to various causes, such as standing for long periods, pregnancy, or an underlying health condition. It is essential to find relief for maintaining comfort and mobility. In this article, we list natural home remedies that can help alleviate swelling and promote overall foot health.

Elevate Your Feet

One of the simplest and most effective remedies for swollen feet is elevation. You can encourage the drainage of excess fluid from your feet and ankles by raising your legs above heart level. Lie down and prop your feet up on pillows or a footstool for 15-20 minutes several times a day to reduce swelling.

Stay Hydrated

Did you know dehydration can exacerbate swelling in the feet and ankles? Ensure you're drinking an adequate amount of water throughout the day to help flush out toxins and excess fluid from your body. Aim for at least 8 glasses of water daily, and avoid excessive consumption of caffeinated or alcoholic beverages, which can contribute to dehydration.

Also Read: From Swelling To Limited Motions: Expert Lists Signs Of Stiff Joints You Should Be Aware Of

Compression Socks

According to a 2023 study, compression socks could be considered a viable option in this scenario, particularly for individuals experiencing swelling resulting from lymphedema, a condition where lymph fluid accumulates and leads to swelling.

These specially designed garments apply gentle pressure to the feet and ankles, preventing fluid buildup and promoting blood flow. Wear compression socks during the day, especially if you spend long periods sitting or standing.

Foot Soaks

You can even soak your feet in warm water to provide immediate relief from swelling and discomfort. Add Epsom salt or essential oils like lavender or peppermint to the water for added relaxation and anti-inflammatory benefits. Soak your feet for 15-20 minutes, then gently pat them dry and moisturise with a hydrating lotion or oil.

Massage

Gentle massage can help stimulate circulation and reduce fluid retention in the feet and ankles. Use your fingertips to apply light pressure in circular motions, starting from the toes and working your way up towards the calves. Adding massage into your daily routine can promote relaxation and alleviate swelling.

Also Read: Swelling In Feet And Ankle: Know Causes From An Expert

Exercise Regularly

Regular physical activity can help prevent fluid buildup in the feet and improve overall circulation. Therefore, engage in low-impact exercises like walking, swimming, or cycling to promote blood flow and reduce swelling. Aim for at least 30 minutes of moderate exercise most days of the week, and be sure to wear supportive shoes to minimise discomfort.

Dietary Adjustments

Certain dietary choices can influence fluid retention and swelling in the body. Limit your intake of sodium, as excess salt can contribute to water retention. Instead, focus on consuming potassium-rich foods like bananas, leafy greens, and avocados, which help regulate fluid balance. According to a 2020 study, men who consume a lot of sodium and are 60 years of age or older are more likely to experience leg swelling.

Additionally, incorporating anti-inflammatory foods, such as ginger, turmeric, and pineapple into your diet may help reduce swelling.

Herbal Remedies

Several herbs have diuretic properties that can help reduce swelling and promote fluid elimination from the body. Consider herbal supplements or teas containing ingredients like dandelion, parsley, or nettle leaf, which can aid in reducing oedema naturally. However, consult with a healthcare professional before using herbal remedies, especially if you have underlying health conditions or are pregnant.

[Disclaimer: This article contains information for informational purposes only, hence we advise you to consult your expert if swelling persists or is accompanied by other concerning symptoms.]

Disclaimer

All possible measures have been taken to ensure accuracy, reliability, timeliness and authenticity of the information; however Onlymyhealth.Com does not take any liability for the same. Using any information provided by the website is solely at the viewers' discretion. In case of any medical exigencies/ persistent health issues, we advise you to seek a qualified medical practitioner before putting to use any advice/tips given by our team or any third party in form of answers/comments on the above mentioned website.

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