When a transplanted organ arrives, it’s like a controlled burn that risks becoming a wildfire. The body’s innate immune system senses damage signals, like heat shock proteins (HSP70), and sounds the alarm, mobilizing dendritic cells to fan the flames of inflammation. Antigen-presenting cells rally T cells to the scene, launching an attack on the foreign tissue. These are the first steps of organ transplant rejection.

Current immunosuppressants act like firefighters putting out the flames once the building (in our case, the tissue) is a blaze. In a new study, Siglec-E in mice (and Siglec-7/9 in humans) acts as an early intervention alert, preventing those fires from spreading in the first place. This receptor binds sialic acid ligands to keep dendritic cells from overreacting. By blocking NF-κB signaling and dampening pro-inflammatory cytokines like TNF-α, Siglec-E keeps the immune response from spiraling out of control.

Without these inhibitory receptors, the immune response surges unchecked, leading to heightened inflammation, accelerated T-cell activation, and faster transplant rejection. By targeting this upstream checkpoint, the researchers propose, it may be possible to quiet the inflammatory blaze at its source—offering a possible therapeutic strategy to protect transplanted organs without broadly suppressing immune function.

Innate immunity’s role in rejection

Current immunosuppressive therapies primarily target T cells, the drivers of the adaptive immune response that recognizes and attacks transplanted organs. These treatments, while effective at reducing rejection, come with a high cost: they broadly suppress immunity, leaving patients vulnerable to infections, cancers, and other complications. Yet despite this aggressive suppression of T cells, many transplants still fail over time. Increasing evidence suggests that early inflammation, mediated by the innate immune system, plays a pivotal role in setting the stage for rejection.

Recognizing this gap, the Mass General Brigham researchers turned their attention upstream, to the body’s first line of defense. Rather than focusing solely on dampening T cells, they explored whether controlling the innate immune response could prevent the inflammatory cascade from spiraling in the first place. By investigating the inhibitory receptor Siglec-E in mice—and its human counterparts, Siglec-7 and Siglec-9—they identified a natural checkpoint that calms overactive immune responses early on.

To test the role of Siglec-E, the team used preclinical mouse models of heart, kidney, and skin transplantation. They found that mice lacking Siglec-E experienced accelerated rejection, heightened inflammation, and increased activation of dendritic cells—the antigen-presenting cells that bridge innate and adaptive immunity. Without Siglec-E, dendritic cells stayed hyperactivated, producing more pro-inflammatory cytokines like TNF-α and IL-6, and driving stronger T-cell responses against the allograft.

When the researchers analyzed human transplant samples, they observed that higher levels of Siglec-7 and Siglec-9 were associated with better graft survival. This finding suggests that the protective role of these inhibitory receptors extends to humans, offering translational potential for new therapies.

By identifying this natural “brake” in the immune system, the study points to a new therapeutic strategy: targeting Siglec-7 and Siglec-9 to modulate dendritic cell activation, reducing inflammation without globally shutting down the immune system. Instead of waiting to suppress T cells after the immune system is already fully mobilized, therapies directed at this pathway could quiet the alarm at its source, preventing the inflammatory cascade that leads to rejection.

A promising target for next-generation transplant therapies

“Regulating innate immune activation is a crucial step in the prevention of transplant rejection and improvement in transplant outcomes,” the researchers state. Prolonged innate immune responses may reduce tolerance while interfering with trained immunity and the adaptive immune response. To maintain a balanced immune response, the innate immune response must be recognized as a front-line defender against excessive inflammation and possible tissue damage.

“By harnessing natural inhibitory pathways like Siglec-E, we can develop safer, more precise therapies that protect transplanted organs without compromising overall immune health,” said Leonardo Riella, MD, PhD, medical director of kidney transplantation at Massachusetts General Hospital.

As a negative regulator of innate immune responses and acute T cell-mediated transplant rejection in mice, Siglec-E offers a potential therapeutic target that may be translatable to humans. This offers hope for a next generation of organ transplant treatments, including longer-lasting transplant success and reducing the need for lifelong immunosuppression.

Researchers headed by a team at the California Institute of Technology developed an ultrasound-guided 3D printing technique that could make it possible to fabricate medical implants in vivo and deliver tailored therapies to tissues deep inside the body—all without invasive surgery. The researchers say the imaging-guided deep tissue in vivo sound printing (DISP) platform utilizes low-temperature–sensitive liposomes (LTSLs) as carriers for cross-linking agents, enabling precise, controlled in situ fabrication of biomaterials within deep tissues.

Reporting on their development in Science (“Imaging-guided deep tissue in vivo sound printing”), first author Elham Davoodi, PhD, and senior, corresponding author Wei Gao, PhD, described proof of concept studies demonstrating in vivo printing within the bladders and muscles of mice, and rabbits, respectively. Gas vesicle (GV)–based ultrasound imaging integrated into the printing platform enabled real-time monitoring of the printing process and precise positioning. In their paper, the authors concluded, “DISP’s ability to print conductive, drug-loaded, cell-laden, and bioadhesive biomaterials demonstrates its versatility for diverse biomedical applications.”

Three-dimensional (3D) bioprinting technologies offer significant promise to modern medicine by enabling the creation of customized implants, intricate medical devices, and engineered tissues, tailored to individual patients, the authors wrote. “However, the implantation of these constructs often requires invasive surgeries, limiting their utility for minimally invasive treatments.”

While in vivo bioprinting—“3D printing” tissue directly within the body—offers a less invasive alternative, it has been limited by challenges such as poor tissue penetration depth, a narrow range of biocompatible bioinks, and the need for printing systems that operate at high resolution with precise, real-time control. “Although near-infrared (NIR) light has been explored as a biosafe energy source for in vivo printing, its applications remain restricted to subcutaneous tissues due to limited light penetration,” the team continued.

To address these barriers, Davoodi and colleagues developed a novel imaging-guided platform, imaging-guided DISP, which uses focused ultrasound and ultrasound-responsive bioinks to precisely fabricate biomaterials directly within the body. These bioinks, or US-inks, combine biopolymers, imaging contrast agents, and temperature-sensitive liposomes carrying crosslinking agents and can be delivered to targeted tissue sites deep within the body via injection or catheter. “US-inks are composed of biopolymers, cross-linking agent-encapsulated LTSLs, and GVs that act as ultrasound imaging contrast agents,” the team further explained. “These bioinks are delivered to the target sites through injection or catheters and are located using an ultrasound imaging setup integrated into a 3D printing platform.”

A focused ultrasound (FUS) transducer, guided by automated positioning and a predefined digital blueprint, triggers localized low-temperature heating (slightly above body temperature) that releases the crosslinker, initiating immediate in situ gel formation. “Localized heating induced by FUS triggers the release of cross-linking agent from the LTSLs, enabling immediate in situ cross-linking of the US-ink.” The bioinks and their resulting gels can be tailored for various functions, including conductivity, localized drug delivery, and tissue adhesion, as well as real-time imaging capabilities.

Davoodi and colleagues validated the DISP technology by successfully printing drug-loaded and functional biomaterials near cancerous sites in a mouse bladder and also deep within rabbit muscle tissue, demonstrating potential applications for drug delivery, tissue regeneration, and bioelectronics. “We validated DISP by successfully printing near diseased areas in the mouse bladder and deep within rabbit leg muscles in vivo, demonstrating its potential for localized drug delivery and tissue replacement,” the team stated.

Further biocompatibility tests revealed no signs of tissue damage or inflammation, and the body cleared unpolymerized US-ink within a week, illustrating the platform’s safety. “The DISP technology offers a versatile platform for printing a wide range of functional biomaterials, unlocking applications in bioelectronics, drug delivery, tissue engineering, wound sealing, and beyond,” the team stated. “By enabling precise control over material properties and spatial resolution, DISP is ideal for creating functional structures and patterns directly within living tissues.”

In a related perspective, Xiao Kuang, PhD, at the University of Wisconsin-Madison, wrote, “Although Davoodi et al. advanced ultrasound 3D printing toward clinical translation, additional refinements are needed to implement the technology for clinical use … A detailed relationship between process conditions, the structure of the printed material, and the resulting properties must be elucidated through careful testing.”

By training machine learning algorithms on data from gut bacteria, scientists from McGill University and their collaborators developed a computational tool to detect patterns in the microbiome that are connected to complex regional pain syndrome (CRPS), a relatively rare condition that affects hundreds of thousands of people worldwide. When they applied the tool to patient samples, it identified a common microbiome signature connected to CRPS n that could lead to advances in how the condition is treated. Details are provided in a new Anesthesiology paper titled, “Altered gut microbiome composition and function in individuals with complex regional pain syndrome.”

CRPS typically develops in a limb after injury or surgery and can lead to long-term disability. It causes severe, persistent pain that is often far worse than the initial injury, along with swelling and changes in skin color and temperature. The condition is challenging to treat, “with patients often experiencing prolonged suffering before receiving appropriate care,” said Amir Minerbi, MD, PhD, senior author on the paper, director of the Institute for Pain Medicine in Haifa, Israel, and senior lecturer at the Technion–Israel Institute of Technology.

The results of this study could help change that. As the researchers noted in the paper, even though the condition has been linked to “dysregulation in several physiologic systems … including aberrant inflammatory and immune responses, vasomotor dysfunction, and nervous system changes,” the exact cause remains unclear, making it harder to treat. Their research could “pave the way for future studies elucidating the pathophysiology of CRPS and exploring new diagnostic aids and treatment modalities.”

Digging into the details, the scientists explain that they used advanced machine learning to analyze gut microbiome samples from two cohorts from Israel and Canada—the samples from Israel were used for training. In total, the scientists analyzed data from 120 microbiome samples as well as over 100 plasma samples from 53 CRPS patients and 52 unrelated controls.

The scientists reported that their algorithm identified significant differences between the gut bacteria of CRPS patients and pain-free individuals. In fact, they successfully predicted CRPS in Canadian patients with over 90% accuracy, according to Emmanuel Gonzalez, PhD, lead author on the paper and a member of the McGill Centre for Microbiome Research. “This is extraordinary because factors like geography, climate, diet, and natural variation between people typically create large microbiome differences. Yet, our AI approach seems to have identified a common ‘microbiome signature’ of CRPS, suggesting microbiome-based diagnostics could work across populations in different countries.”

Furthermore, even patients whose symptoms cleared after limb amputation still had the same gut bacteria pattern linked to CRPS. That suggests that the gut microbiome “might make some people more prone to developing CRPS, with an injury or other event triggering the condition,” said Yoram Shir, MD, a professor in the department of anesthesia at McGill’s Faculty of Medicine and Health Sciences.

After spending years tracing the origin and migration pattern of an unusual type of immune cell in mice, researchers headed by a team at The Ohio State University College of Medicine have shown how the activity of “good” microbes in the gut is linked to rheumatoid arthritis (RA) and, potentially, other autoimmune diseases.

Scientists first reported in 2016 that specific gut microbes known as commensal bacteria, which cause no harm and often contribute to host health, set off production and release of a gut-originated T cell that drives up body-wide autoimmune disease in mice. Since then, the team has focused on explaining this unexpected twist in the typically harmonious relationship between these microbes and the body.

The gut is where the action begins, but the overall outcome can be attributed to T cells’ “plasticity”—their flexibility to respond to a changing environment, such as in our body’s barrier, the gut.

The research indicates that reprogrammed T helper cells adopt characteristics of a new T helper cell type while preserving some of their original traits, making them “super powerful and potent—and if you are dealing with autoimmune disease, that’s bad news,” said senior and corresponding study author Hsin-Jung Joyce Wu, BVM, PhD professor of internal medicine, division of rheumatology and immunology, at The Ohio State University College of Medicine. “This is really the first time it’s been shown that T cell plasticity, which typically occurs in the gut, can have this dramatic impact outside the gut with systemic impact on autoimmune disease.”

The newly reported findings likely have relevance to human patients, Wu said. Many of the gene expressions detected in these abnormal cells in mice also exist in the same cells in people with rheumatoid arthritis. Wu is senior author of the team’s paper in Nature Immunology, titled “Aberrant T follicular helper cells generated by TH17 cell plasticity in the gut promote extraintestinal autoimmunity.” In their paper the team concluded, “Our findings offered a mechanism whereby T cell plasticity, a process originating in the gut and aided by gut microbiota, powerfully promotes autoimmunity at gut-distal sites.”

“Autoimmune diseases have risen steeply in the industrialized world,” the authors wrote. An estimated 18 million people worldwide are affected by rheumatoid arthritis, a chronic autoimmune disease-causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. Though the exact cause is unknown, genetics and environmental exposures—such as smoking and changes of gut commensal bacteria, or dysbiosis—are among the risk factors.

The abnormal T cells in question is called a T follicular helper 17 (TFH17) cell—meaning it functions as a TFH cell but also displays T helper 17 (TH17) cell signatures. Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells’ backstory. “An excessive TFH cell response can lead to overproduction of autoantibodies (auto-Ab) and autoimmunity,” the team further noted, while “Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients.”

These cells have been a puzzle, Wu said, because the conventional TFH cells are expected to be nonmobile, and just reside in B cell follicles to help B cells, another immune cell type critical for the development of RA. “T follicular helper (TFH) cells are a subset of CD4+ T cells, specializing in B cell help,” they pointed out. “Unlike other T effector cells, conventional TFH cells are not very mobile as they are mostly confined to the B cell follicles where they originated.”

However, in contrast with conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce the proinflammatory protein IL-17. “Circulating T follicular helper 17 (cTFH17) cells are a subset of T cells sharing both TFH and T helper 17 (TH17) cell signatures, which are found in the blood of numerous types of autoimmune patients,” the investigators explained.

Following their 2016 study, work in Wu’s lab has now discovered that the systemic TFH cells traced back to Peyer’s patches (PP), lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria (SFB), are enriched with TFH17 cells.

Studies in fate-mapping mouse models showed that the hybrid cells derived from T helper 17 cells in the gut transformed into T follicular helper cells inside Peyer’s patches, and that the segmented filamentous bacteria enhanced the cell reprogramming process. “… using the TH17 cell fate-mapping mice to track TH17-derived cells, we found that a large proportion of TH17 cells transdifferentiated into the TFH cells in PPs,” they further stated. “This TH17 cell reprogramming was driven by the transcription factor c-Maf and SFB further enhanced this process.”

Wu noted, “The key is T cell plasticity only happens in very few places, which is why it’s been overlooked—the dominant place to find them is in the gut barrier. And that’s one of few places in the body where the environment can change from one second to the next, and therefore induction of T cell plasticity occurs to accommodate the ever-changing environmental challenge.”

The team then used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body. “That’s how we knew they were really traveling,” Wu said. Importantly, these cells also acquire a stronger capability to help B cells compared to conventional TFH cells. “That’s what makes them ultra-pathogenic TFH cells in RA, a systemic disease, because they are very mobile and can potently help B cells,” she said.

To demonstrate the hazard associated with these abnormal TH17-derived TFH (TFH17Der) cells, the researchers compared RA development in genetically susceptible mouse models injected with only conventional TFH cells (control group) or conventional TFH cells mixed in with around 20% of TH17-derived TFH cells.

Substituting a small number of the conventional cells with these aberrant TFH cells increased the arthritis-related ankle thickening in mice by 4.8-fold compared to control mice, a finding that took Wu and colleagues by surprise. “The biological significance of TFH17Der cells was demonstrated by the gain-of-function study showing that a minor percentage of the TFH17Der cells boosted ankle thickening by 4.8-fold compared to the control group,” they wrote.

Researchers also sequenced the gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models and found that they shared several similarities with those of TFH cells circulating in the blood of people with RA—including the gut signature, hinting that a similar mechanism is behind human disease as well. Compared with healthy controls, the investigators stated, “… the murine PP TFH17Der cell signature was also enriched in patients with RA … and cTFH cells isolated from patients with RA displayed enhanced gene expression associated with TFH cell function, TH17 cells and mucosal origin.”

“That, to me, was exciting, to find this cross-species signature, which suggests the translational potential of this research,” Wu said. “We are hoping to improve patients’ health and life. For the future, as TFH17 cells can be found in other type of autoimmune patients, such as lupus patients, if we can determine that these abnormal TFH cells are a potential target not just for RA, but across autoimmune diseases, that would be very useful.” The authors further stated, “It will be interesting to investigate whether the findings are applicable to other autoimmune diseases as well as conditions outside autoimmunity.”