Immunological Barrier Research Articles

Immunologic barriers in liver transplantation: a single-cell analysis of the role of mesenchymal stem cells.

This study aimed to analyze the biomarkers that may reliably indicate rejection or tolerance and the mechanism that underlie the induction and maintenance of liver transplantation (LT) tolerance related to immunosuppressant or mesenchymal stem cells (MSCs). LT models of Lewis-Lewis and F344-Lewis rats were established. Lewis-Lewis rats model served as a control (Syn). F344-Lewis rats were treated with immunosuppressant alone (Allo+IS) or in combination with MSCs (Allo+IS+MSCs). Intrahepatic cell composition particularly immune cells was compared between the groups by single-cell sequencing. Analysis of subclusters, KEGG pathway analysis, and pseudotime trajectory analysis were performed to explore the potential immunoregulatory mechanisms of immunosuppressant alone or combined with MSCs. Immunosuppressants alone or combined with MSCs increases the liver tolerance, to a certain extent. Single-cell sequencing identified intrahepatic cell composition signature, including cell subpopulations of B cells, cholangiocytes, endothelial cells, erythrocytes, hepatic stellate cells, hepatocytes, mononuclear phagocytes, neutrophils, T cells, and plasmacytoid dendritic cells. Immunosuppressant particularly its combination with MSCs altered the landscape of intrahepatic cells in transplanted livers, as well as gene expression patterns in immune cells. MSCs may be included in the differentiation of T cells, classical monocytes, and non-classical monocytes. These findings provided novel insights for better understanding the heterogeneity and biological functions of intrahepatic immune cells after LT treated by IS alone or in combination with MSCs. The identified markers of immune cells may serve as the immunotherapeutic targets for MSC treatment of liver transplant rejection.

Conquering immunological barrier in kidney transplantation: ABO incompatible transplantation

No abstract available

Expert consensus on pre-exposure rabies prophylaxis

Pre-exposure rabies prophylaxis, also known as immunoprophylaxis before exposure to rabies, refers to preventive rabies vaccination for individuals at risk of rabies infection before rabies exposure, which is one of the important strategies for rabies prevention. Pre-exposure rabies prophylaxis can reduce the risk of individual rabies and reduce the cost of post-exposure prophylaxis by establishing an immunologic barrier in advance and the memory immune response after the booster. In view of the current situation that clinicians in China have relatively insufficient knowledge of pre-exposure rabies prophylaxis, the Rabies Prevention and Control Committee of the Chinese Preventive Medicine Association and Animal Injury Treatment Branch of China Association for Disaster and Emergency Rescue Medicine organized domestic experts in relevant fields to write this expert consensus in accordance with the latest guidelines, expert consensus, and the latest clinical evidence. This consensus describes the concept and significance of pre-exposure rabies prophylaxis, immunization procedures and cost-effectiveness respectively, and puts forward recommendations on pre-exposure rabies prophylaxis strategies. It is hoped that this consensus can improve clinicians' understanding of pre-exposure rabies prophylaxis and increase the rate of pre-exposure rabies prophylaxis among people at high risk of exposure in China.

Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair.

The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood-brain-barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated. Targeting and activation of CB2R was accomplished by a novel and highly specific chromenopyrazole based CB2R agonist, PM289. This study demonstrates that CB2R upregulation is induced as early as 8 h in the cortical vasculature in an experimental mouse model of TBI. Unlike CB2R, CB1R was marginally detected and not significantly induced. In the human brain endothelial cell line, hCMEC/D3 cells, similar induction of CB2R was observed upon stimulation with TNFα. Analysis of transendothelial electrical resistance shows that PM289 markedly prevented the barrier-leakiness induced by TNFα. The BBB is also responsible for maintaining an immunological barrier. The five-fold increase in ICAM1 expression in stimulated endothelial cells was significantly diminished due to CB2R activation. Utilizing wounding assays, results showed that wound repair could be accomplished in nearly half the time when the novel CB2R agonist is present compared to the untreated control. Lastly, mechanistically, the effects of CB2R may be explained by the observed inhibition of the p65 NFκB subunit. Overall, these studies support the notion that targeting and activating CB2R in the brain vasculature could aid in BBB and vascular protection in the context of neuroinflammation.

Extracellular matrix rigidity modulates physical properties of subcapsular sinus macrophage-B cell immune synapses

Subcapsular sinus macrophages (SSMs) play a key role in immune defense by forming immunological barriers that control the transport of antigens from lymph into lymph node follicles. SSMs participate in antibody responses by presenting antigens directly to naive B cells and by supplying antigens to follicular dendritic cells to propagate germinal center reactions. Despite the prominent roles that SSMs play during immune responses, little is known about their cell biology because they are technically challenging to isolate and study in vitro. Here, we used multicolor fluorescence microscopy to identify lymph node-derived SSMs in culture. We focused on the role of SSMs as antigen-presenting cells, and found that their actin cytoskeleton regulates the spatial organization and mobility of multivalent antigens (immune complexes [ICs]) displayed on the cell surface. Moreover, we determined that SSMs are mechanosensitive cells that respond to changes in extracellular matrix rigidity by altering the architecture of the actin cytoskeleton, leading to changes in cell morphology, membrane topography, and IC mobility. Changes to extracellular matrix rigidity also modulate actin remodeling by both SSMs and B cells when they form an immune synapse. This alters synapse duration but not IC internalization nor NF-κB activation in the B cell. Taken together, our data reveal that the mechanical microenvironment may influence B cell responses by modulating physical characteristics of antigen presentation by SSMs.

Placental perfusion imaging on 3Tesla magnetic resonance imaging using pseudo-continuous arterial spin labelling: an initial experience

BackgroundDuring pregnancy, the placenta plays an important role in the development of the fetus by supplying it with oxygen and nutrition, eliminating waste, and acting as an immunological barrier. Pseudo-continuous arterial spin labelling (pCASL) MRI was recently shown to be a promising sequence for measuring perfusion in the placenta. The aim was to obtain the perfusion measurements of the placenta in normal pregnancies using 3 Tesla MRI from 19 to 38 weeks of gestational age.ResultsThis was a cohort observational study. One hundred and sixty (160) singleton pregnancies from 19 to 38 weeks of gestational age were included. A 3D pCASL sequence was performed in the axial plane for placental blood flow (PBF). Data post-processing was performed on a workstation using Ready View software for 3D ASL with automated generation of quantitative placental pattern-based morphometry (PBM). The mean values of placental perfusion were extracted by averaging the data obtained. A significant positive correlation was observed between the PBF and increasing GA using Karl Pearson’s coefficient of correlation values (r-value 0.77, p-value < 0.001), respectively. Average PBF values from 19 to 38 weeks were (89.4 ± 13.5 to 155.3 ± 2.8 ml/100 g/min). According to our intra-class correlation coefficient (ICC), inter-observer reproducibility of placental blood flow shows good agreement between observers (0.98).ConclusionsNormal PBF values using ASL in 3 T MRI from 19 to 38 weeks of gestational age were provided. Statistical analysis revealed a significant positive correlation between gestational age and placental blood flow. In the future, it may help to identify placental perfusion abnormalities like placental insufficiency, preeclampsia, and fetal growth restriction (FGR).

The Role of the Duffy Blood Group Antigens in Renal Transplantation and Rejection. A Mini Review.

Finding a compatible donor for kidney transplant candidates requires overcoming immunological barriers such as human leukocyte antigens (HLA) compatibility and ABO compatibility. Emerging data suggest a role for red blood cell antigens (RCA) in renal transplant outcomes. The incidence of RCA alloimmunization is high in chronically transfused individuals, such as end stage renal disease patients, but whether antibodies to RCA can mediate renal graft rejection remains debatable. The Duffy blood group antigens (Fy) has been shown to be expressed in the kidney, among other tissues. There are some data to suggest that donor-recipient Fy mismatches may increase the risk for chronic allograft damage and that anti-Fy antibodies may be involved in renal graft rejection, however, while it is routine to screen renal transplant candidates for ABO antigens, detailed RCA phenotyping of the donor kidney is not routinely tested. In this paper, we review the current data on the role of Fy in renal transplantation and discuss the potential mechanisms of its biological function.

Overcoming Immunological Barriers in Xenotransplantation: A Historical Review of Previous Research and Future Directions

Overcoming Immunological Barriers in Xenotransplantation: A Historical Review of Previous Research and Future Directions

Effects of Investigational Moisturizers on the Skin Barrier and Microbiome following Exposure to Environmental Aggressors: A Randomized Clinical Trial and Ex Vivo Analysis.

The skin microbiota barrier participates in skin barrier function in addition to the physical, chemical, and immunological protective barriers, and is affected by environmental aggressors and skincare regimens. To better understand the exact effects of real-life environmental conditions on the skin and determine the protective methods, this study investigates the effects of three topical cosmetic moisturizers (water gel moisturizers with/without yeast extract (Moisturizers K and C) and a thick-emulsion cream moisturizer (Moisturizer L)) on clinical and skin microbiome endpoints in the presence of environmental aggressors during an 8-week, randomized controlled, triple-blind clinical trial with 110 participants, and molecular- as well as biomarker-level endpoints on ex vivo skin explants after exposure to simulate urban environmental conditions. The results show that all moisturizers are well-tolerated and improve skin barrier function and surface moisture content from the baseline, and the improvement is maintained at the last analysis point (3 days after trial completion). Compared with the untreated control areas (samples taken from the upper chest), treatment with Moisturizer K prevented a reduction in bacterial and fungal richness, and increased the change ratio of the relative abundance of commensal bacteria, such as Staphylococcus epidermidis and Ralstonia, at the treated sites (samples taken from the forehead). Moreover, Moisturizer K-treated ex vivo skin explants had higher levels of caspase 14 (a marker of skin barrier function), collagen I, and elastin (structure components), and lower levels of aryl hydrocarbon receptor (AHR; activated by air pollutants) and interleukin-6 (IL-6) than those in explants treated with other moisturizers and in the untreated areas of the skin. These results suggest that a skin postbiotic moisturizer with yeast extract supports the regulation of the skin's microbiome balance and may provide a holistic barrier (involving skin microbiome, physical, chemical, and immune barriers) to protect the skin against environmental aggressors.

Immune cells in skin inflammation, wound healing, and skin cancer.

Given the self-evident importance of cutaneous immunity in the maintenance of body-surface homeostasis, disturbance of the steady-state skin is inextricably intertwined with dysfunction in cutaneous immunity. It is often overlooked by people that skin, well-known as a solid physical barrier, is also a strong immunological barrier, considering the abundant presence of immune cells including lymphocytes, granulocytes, dendritic cells, and macrophages. What's more, humoral immune components including cytokines, immunoglobulins, and antimicrobial peptides are also rich in the skin. This review centers on skin inflammation (acute and chronic, infection and aseptic inflammation), wound healing, and skin cancer to elucidate the elaborate network of immune cells in skin diseases.

Az egészséges bőr regionális eltérései

As one of our most important barrier organs, our skin has complex functions, both to connect us with the outside world and to protect us from its harmful effects. According to literature data, skin barrier can be divided into 4 functional units: microbial, chemical, physical and immunological barriers. The microbial and chemical barriers have been previously shown to exhibit different characteristics in topographically distinct skin regions. The research group at the Department of Dermatology, University of Debrecen, Hungary, has investigated whether the physical and immunological barriers also show differences in different skin areas. This article summarises the working group’s research on this topic, which demonstrated that, in addition to the microbial and chemical barriers, the other two barriers also differ in distinct skin regions. These differences may explain the characteristic localisation of certain region-specific skin diseases.

The direct and gut microbiota-mediated effects of dietary bile acids on the improvement of gut barriers in largemouth bass (Micropterus salmoides).

Fish gut barrier damage under intensive culture model is a significant concern for aquaculture industry. This study aimed to investigate the effects of bile acids (BAs) on gut barriers in Micropterus salmoides. A germ-free (GF) zebrafish model was employed to elucidate the effects of the direct stimulation of BAs and the indirect regulations mediated by the gut microbiota on gut barrier functions. Four diets were formulated with BAs supplemented at 0, 150, 300 and 450mg/kg, and these 4 diets were defined as control, BA150, BA300 and BA450, respectively. After 5 weeks of feeding experiment, the survival rate of fish fed with BA300 diet was increased (P<0.05). Histological analysis revealed an improvement of gut structural integrity in the BA150 and BA300 groups. Compared with the control group, the expression of genes related to chemical barrier (mucin, lysozyme and complement 1) and physical barrier (occludin and claudin-4) was increased in the BA150 and BA300 groups (P<0.05), and the expression of genes related to immunological barrier (interleukin [IL]-6, tumor growth factor β, IL-10, macrophage galactose-type lectin and immunoglobulin M [IgM]) was significantly increased in the BA300 group (P<0.05), but the expression of genes related to chemical barrier (hepcidin) and immunological barrier (IL-1β, tumor necrosis factor-α, IL-6 and arginase) was significantly decreased in the BA450 group (P<0.05). Gut microbiota composition analysis revealed that the abundance of Firmicutes was augmented prominently in the BA150 and BA300 groups (P<0.05), while that of Actinobacteriota and Proteobacteria showed a downward trend in the BA150 and BA300 groups (P>0.05). The results of the gut microbiota transferring experiment demonstrated an upregulation of gut barrier-related genes, including immunoglobulin Z/T (IgZ/T), IL-6, IL-1β and IL-10, by the gut microbiota transferred from the BA300 group compared with the control (P<0.05). Feeding the BA300 diet directly to GF zebrafish resulted in enhanced expression of IgM, IgZ/T, lysozyme, occludin-2, IL-6 and IL-10 (P<0.05). In conclusion, BAs can improve the gut barriers of fish through both direct and indirect effects mediated by the gut microbiota.

Excessive dietary soluble arabinoxylan impairs the intestinal physical and immunological barriers via activating MAPK/NF-κB signaling pathway in rainbow trout (Oncorhynchus mykiss)

Arabinoxylan (AX) has been deemed as an antinutritional factor, but limited information has addressed the effects of dietary AX on intestinal health of fish. The present study investigated the effects of dietary AX on intestinal mucosal physical and immunological barriers of rainbow trout (Oncorhynchus mykiss). Five isoproteic and isolipidic experimental diets (AXE, AX0, AX2.5, AX5 and AX10) were formulated to contain 0.03% arabinoxylanase as well as 0%, 2.5%, 5% and 10% AX, respectively. Each diet was randomly distributed to triplicate groups of 35 juvenile (average weight 3.14 ± 0.02 g) per tank in a rearing system maintained at 17 ± 1 °C for 9 weeks. Dietary AX supplementation regardless of inclusion levels significantly (P < 0.05) depressed the growth performance and feed utilization. The plasma endothelin-1 and d-lactic acid contents as well as diamino oxidase activity were significantly higher in fish fed diet AX10 compared to fish fed diet AX0. Dietary inclusion of 5–10% AX resulted in decreased intestinal villus height, goblet cell number and desmosome density, increased crypt depth, short and irregular microvilli, widened intercellular space; down-regulated the mRNA levels of occludin in hindgut, claudin3 and ZO-1 in foregut and midgut, but up-regulated the mRNA levels of claudin12 and claudin15 in midgut as well as claudin23 in foregut, midgut and hindgut. Furthermore, dietary 5–10% AX supplementation decreased the midgut and hindgut complement 3, complement 4 and sIgT contents as well as the midgut IgM and hindgut IL-10 contents. Conversely, the hindgut TNF-α and IL-6 contents increased with the rising dietary AX level. RT-qPCR demonstrated that the pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12β, IFN-γ, and TNF-α) and pIgR mRNA levels in midgut and hindgut were up-regulated by dietary AX inclusion of 5–10% AX. Meanwhile, the mRNA levels of p38 MAPK, IκBα, and NF-κB p65 in midgut and hindgut raised gradually with the increasing dietary AX content. The Western blot results showed that the protein expression levels of p38 MAPK and NF-κB generally increased with the rising dietary AX content. Dietary treatment with 0.03% arabinoxylanase did not affect the growth performance and intestinal health of rainbow trout (P > 0.05). In conclusion, excessive dietary AX inclusion (5–10%) increased the intestinal permeability and induced the intestinal inflammatory response via activating MAPK/NF-κB signaling pathway, and ultimately damaged the intestinal barrier function of rainbow trout.

The immunological and structural epidermal barrier dysfunction and skin microbiome in atopic dermatitis-an update.

Atopic dermatitis (AD) is a common, chronic and relapsing inflammatory skin disease with various clinical presentations and combinations of symptoms. The pathophysiology of AD is complex and multifactorial. There are several factors involved in the etiopathogenesis of AD including structural and immunological epidermal barrier defect, imbalance of the skin microbiome, genetic background and environmental factors. Alterations in structural proteins, lipids, proteases, and their inhibitors, lead to the impairment of the stratum corneum which is associated with the increased skin penetration and transepidermal water loss. The elevated serum immunoglobulin E levels and blood eosinophilia have been shown in the majority of AD patients. Type 2 T-helper cell immune pathway with increased expression of interleukin (IL)-4, IL-5, and IL-13, has an important role in the etiopathogenesis of AD. Both T cells and keratinocytes contribute to epidermal barrier impairment in AD via a dynamic interaction of cytokines and chemokines. The skin microbiome is another factor of relevance in the etiopathogenesis of AD. It has been shown that during AD flares, Staphylococcus aureus (S. aureus) colonization increased, while Staphylococcus epidermidis (S. epidermidis) decreased. On the contrary, S. epidermidis and species of Streptococcus, Corynebacterium and Propionibacterium increased during the remision phases. However, it is not clear whether skin dysbiosis is one of the symptoms or one of the causes of AD. There are several therapeutic options, targeting these pathways which play a critical role in the etiopathogenesis of AD. Although topical steroids are the mainstay of the treatment of AD, new biological therapies including IL-4, IL-13, and IL-31 inhibitors, as well as Janus kinase inhibitors (JAKi), increasingly gain more importance with new advances in the therapy of AD. In this review, we summarize the role of immunological and structural epidermal barrier dysfunction, immune abnormalities, impairment of lipids, filaggrin mutation and skin microbiome in the etiopathogenesis of AD, as well as the therapeutic options for AD and their effects on these abnormalities in AD skin.

Joseph E. Murray's Struggle to Transplant Kidneys: Failure, Individuality, and Plastic Surgery, 1950-1965.

This paper offers a historical analysis of the American plastic surgeon and Nobel laureate Joseph E. Murray's kidney transplantation. After succeeding in the first kidney transplantation between monozygotic twins in 1954, he transplanted kidneys between genetically distinct people after X-radiation and immunosuppressants. Amid these achievements, however, Murray encountered numerous failures, which he thought were closely intertwined with each patient's physiological and pathological individuality. As he appropriated his expertise in plastic surgery for kidney transplantation, this individuality became a major issue that he had to cope with in his efforts to avoid failures. To him, kidney transplantation could fail because of each individual's immunological barrier or constitutional singularity that could engender unexpected complications. Although he could neither explain nor control many of these failures, I argue that his unsuccessful work and patient individuality played multiple roles in shaping his operations as a plastic surgeon. They structured the path of his surgical research, made sense of it, defended him from criticism, and formed the way that he presented the results of his work with an immunological implication. Consequently, Murray, with little scientific training, articulated an important dimension of immunological tolerance relevant to clinical settings.

Anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) for adoptive cell immunotherapy.

Equipping multiple functionalities on adoptive effector cells is essential to overcome the complex immunological barriers in solid tumors for superior antitumor efficacy. However, current cell engineering technologies cannot endow these functionalities to cells within a single step because of the different spatial distributions of targets in one cell. Here, we present a core-shell anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) to achieve one-step multiplexing cell engineering for multifunctional cell construction. Through fusing with the M1 macrophage membrane, ARMFUL inserts an anti-CD47 (aCD47)-modified lipid shell onto the surface and simultaneously delivers colony-stimulating factor 1 receptor inhibitor BLZ945-loaded core into the cytoplasm. The surface-presenting aCD47 boosts macrophage's phagocytosis against the tumor by blocking CD47. The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.

Protective Effects of Bacteriocin-Producing Lactiplantibacillus plantarum on Intestinal Barrier of Mice.

Bacteriocins are crucial metabolites of probiotics that display beneficial functions. The intestinal barrier is an important target on which probiotics exert their intestinal health activity. However, the impacts of bacteriocin-producing probiotics on the intestinal barrier are unclear. In this study, the effects of bacteriocin-producing Lactiplantibacillus plantarum Q7 and L. plantarum F3-2 on the intestinal barrier of mice were explored. It was shown that L. plantarum Q7 promoted the expression of mucin MUC2 to enhance the protection provided by the intestinal mucus layer. L. plantarum Q7 up-regulated the gene expression of intestinal tight junction proteins ZO-1 and JAM-1 significantly, and L. plantarum F3-2 up-regulated ZO-1 and Claudin-1 markedly, which exhibited tight junction intestinal barrier function. The two strains promoted the release of IgA and IgG at varying degrees. The antimicrobial peptide gene RegIIIγ was up-regulated markedly, and the gene expression of inflammatory cytokines appeared to exhibit an upward trend with L. plantarum Q7 treatment, so as to enhance intestinal immune regulation function. Furthermore, L. plantarum Q7 and L. plantarum F3-2 increased the abundance of the beneficial bacteria Muribaculaceae, inhibited the growth of the harmful bacteria Parabacteroides, and facilitated the synthesis of total short-chain fatty acids (SCFAs), which seemed to favor the prevention of metabolic diseases. Our results suggested that L. plantarum Q7 and L. plantarum F3-2 showed strain specificity in their protective effects on the intestinal chemical, physical, immunological and biological barriers of mice, which provided theoretical support for the selective utilization of bacteriocin-producing strains to regulate host health.

Co-evolution of immunity and seasonal influenza viruses.

Seasonal influenza viruses cause recurring global epidemics by continually evolving to escape host immunity. The viral constraints and host immune responses that limit and drive the evolution of these viruses are increasingly well understood. However, it remains unclear how most of these advances improve the capacity to reduce the impact of seasonal influenza viruses on human health. In this Review, we synthesize recent progress made in understanding the interplay between the evolution of immunity induced by previous infections or vaccination and the evolution of seasonal influenza viruses driven by the heterogeneous accumulation of antibody-mediated immunity in humans. We discuss the functional constraints that limit the evolution of the viruses, the within-host evolutionary processes that drive the emergence of new virus variants, as well as current and prospective options for influenza virus control, including the viral and immunological barriers that must be overcome to improve the effectiveness of vaccines and antiviral drugs.

Sertoli Hücresi ve Kan-Testis Bariyeri

The Sertoli cell is a critical somatic cell that initiates the development of testicular morphology and determines important parameters for spermatogenic function. The blood-testis barrier, also known as the Sertoli cell barrier and one of the tightest tissue barriers in the mammalian body, is an immunological barrier to separate post meiotic germ cell antigens from the systemic circulation. Additionally, creating a unique microenvironment for the development of spermatocytes that exceed into the adluminal compartment from the leptotene stage. It restricts the passage of substances such as paracrine factors, electrolytes, hormones, water, and biological molecules to the apical part of the seminiferous tubule. It separates spermatogenic cells from toxic and drug-containing environmentally harmful substances, hormones, and biomolecules in the systemic circulation. This nearly impenetrable barrier prevents proteins, including antibodies, from reaching the spermatogenic cells. It also prevents protein leakage from developing spermatogenic cells and forming an immune response. This review explains Sertoli's functional properties, the testis barrier's molecular structure, the substances involved in the barrier dynamics, and their importance in realizing spermatogenesis.

The history of cardiac xenotransplantation: early attempts, major advances, and current progress.

In light of ongoing shortage of donor organs for transplantation, alternative sources for donor organ sources have been examined to address this supply-demand mismatch. Of these, xenotransplantation, or the transplantation of organs across species, has been considered, with early applications dating back to the 1600s. The purpose of this review is to summarize the early experiences of xenotransplantation, with special focus on heart xenotransplantation. It aims to highlight the important ethical concerns of animal-to-human heart xenotransplantation, identify the key immunological barriers to successful long-term xenograft survival, as well as summarize the progress made in terms of development of pharmacological and genetic engineering strategies to address these barriers. Lastly, we discuss more recent attempts of porcine-to-human heart xenotransplantation, as well as provide some commentary on the current concerns and possible applications for future clinical heart xenotransplantation.