HSCT is indicated for hematologic malignancies, non-malignant blood disorders, primary immunodeficiencies, severe autoimmune diseases, and congenital metabolic disorders, serving as a curative or life-extending therapy by replacing dysfunctional hematopoietic and immune systems (14). In HSCT, HLA matching (especially at HLA-A, -B, -C, and -DR) is paramount to prevent graft failure, GvHD, and other complications. A 10/10 match (for both alleles of HLA-A, -B, -C, -DR, and -DQ) is preferred for unrelated donor transplants, while mismatches at a single locus (e.g., 9/10) are acceptable but increase the risk of GvHD. It is worth noting that having national and international registries enables highly compatible donors to be identified rapidly and efficiently. Patients lacking HLA-identical donors can be treated with haploidentical transplants that allow the use of HSC from an allogeneic half-matched donor (5/10 match), who is typically a family member. However, they often require additional interventions to mitigate risks, such as T-cell depletion or post-transplant immunomodulation. HLA-C and HLA-DP matching has also been shown to improve outcomes in HSCT (15).

Kidney transplantation is indicated for patients with end-stage renal disease (ESRD) or advanced chronic kidney disease (CKD) who present irreversible loss of kidney function, requiring renal replacement therapy to improve survival and quality of life. Cross-matching and DSA testing are crucial adjuncts to HLA matching for kidney transplants. Acceptable mismatches depend on sensitization and availability of donors. HLA-A, -B and -DR matching has a direct impact on long-term graft survival, while HLA-DR mismatches tend to be the most immunogenic and impactful. HLA-B mismatches also carry a strong risk due to high polymorphism. HLA-A mismatches are important but generally considered less immunogenic than -DR or -B. Patients with higher HLA matches require less immunosuppression and have a reduced risk of AMR. HLA matching is often prioritized in living donor kidney transplantation or for younger recipients where longevity of the graft is critical (16).

Interestingly, ABO antigens are expressed on kidney endothelial and epithelial surfaces, and their presence on allograft tissue can lead to higher short-term hyperacute or acute AMR, although with good management, long-term outcomes can approach those of compatible transplants. It is worth noting that blood group B kidney recipients experience longer waiting times than other ABO groups prior to transplantation (17). The prevalence of group B is higher in African Americans and Asian Americans and thus these ethnic minorities are the most affected populations within the group B cohort (18).

Apart from HLA/ABO matching, the effect of other factors on post-transplant outcomes, including viral serology, age and size mismatch, mismatch in other HLA antigens (e.g. HLA-C and HLA-DQ), and eplet matching, has become increasingly recognized. Of note, kidney transplant recipients who experience rejection can return to dialysis, a situation that is not paralleled in other transplantation settings.

Heart transplantation is indicated for patients with end-stage heart failure due to conditions such as dilated or ischemic cardiomyopathy, congenital heart disease, or refractory ventricular arrhythmias, who have severe symptoms despite medical, surgical, or device-based therapies and meet criteria for irreversible hemodynamic compromise. Although, where feasible, HLA-A, -B, and -DR matching is considered, primarily to reduce the risk of sensitization in re-transplantation cases, no specific HLA match requirement is universally mandatory given that transplantation may not be delayed due to clinical urgency. Consequently, immunosuppression protocols are heavily relied upon in heart transplants, much more than in kidney transplantation, since graft rejection is usually fatal (19). This may explain why no further decline in the organ survival rate was found as the number of HLA mismatches increased from three to six (19, 20). As a consequence of intensive immunosuppressive treatment, high rates of malignant lymphomas are reported in heart transplant patients (21).

Transplantation of hearts from ABO-incompatible donors is contraindicated because of the risk of hyperacute rejection. This contraindication may not apply to infants younger than 2 years, who do not yet produce antibodies against T-cell-independent antigens. However, use of donors with minor ABO mismatches is also a safe and feasible option in older children and adult patients (22–24).

Liver transplantation is indicated for patients with end-stage liver disease, acute liver failure, or metabolic disorders affecting hepatic function due to conditions such as cirrhosis, hepatocellular carcinoma within transplant criteria, or genetic liver diseases, when no alternative treatment can prevent life-threatening complications or hepatic decompensation. In liver transplantation, no stringent HLA matching is required since the liver is considered immunologically privileged compared to other organs due to its inherent tolerogenic properties. Of note, ABO compatibility is more critical than HLA matching for liver transplants (25–27).

Lung transplantation is indicated for patients with end-stage pulmonary disease, such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, cystic fibrosis, or pulmonary arterial hypertension, who have severe respiratory failure and reduced life expectancy. Matching at HLA-A, -B, and -DR may improve long-term outcomes, particularly chronic lung allograft dysfunction (CLAD) and bronchiolitis obliterans syndrome (BOS). However, issues related to organ availability mean that perfect matching is not strictly required. High levels of pre-transplant sensitization increase the risk of rejection. Opelz and collaborators analyzed a large series of lung transplant procedures followed up on for 5 years, demonstrating that a high number of HLA mismatches or, surprisingly, zero mismatches, unfavorably impacts graft survival rates (28). Recently, HLA-C mismatches have been described as beneficial in lung transplantation due to a reduced incidence of CLAD in recipients with HLA-C mismatching (29).

Pancreas and pancreatic islet transplantation are indicated for patients with type 1 diabetes mellitus experiencing severe glycemic instability, recurrent hypoglycemia unawareness syndrome, or secondary complications, particularly when simultaneous kidney transplantation is required due to ESRD or when intensive insulin therapy fails to achieve metabolic control. HLA-A, -B, and -DR matching is ideal in pancreas transplantation but is not always feasible. According to the results published by Rudolph et al., the risk of acute rejection increases significantly at four or more mismatches, especially when they involve the HLA-B or -DR locus (30). In contrast, recent results suggest that HLA matching is not associated with improved graft survival or a reduction in acute rejection (31).

Interestingly, success in pancreas transplantation is more reliant on careful immunosuppression and ABO compatibility. Despite this, there have been successful cases of ABO-incompatible pancreas transplantation, particularly in simultaneous pancreas-kidney (SPK) procedures. These cases usually involve intensive immunosuppressive regimens and pre-transplant antibody removal strategies (e.g., plasmapheresis, rituximab) to lower the risk of rejection.

Pancreatic islet cell transplants often require less stringent matching due to i) advances in immunosuppressive options, and ii) the infusion of a small amount of islets into the liver via the portal vein. In this context, a recent study suggests that recipients with HLA-DR matching, excluding diabetogenic HLA-DR3 and -DR4 alleles, maintained higher rates of insulin independence 5 years after transplantation compared to those with mismatching (32). Of note, the purity of islet preparations has a direct impact on rejection due to contamination with pancreatic exocrine tissue components and acinar tissue expressing ABH antigens (33). Additionally, certain HLA-DQ antigens have been associated with improved graft survival (34).

Corneal transplantation, also known as keratoplasty, can be complete (penetrating keratoplasty) or partial (endothelial keratoplasty) and is indicated for patients with corneal opacification, thinning, or structural damage due to conditions such as keratoconus, corneal dystrophies, infections, trauma, or scarring, when visual rehabilitation or ocular integrity cannot be achieved through other interventions. Although no HLA matching is typically required for low-risk corneal transplants due to the immune-privileged status of the corneal tissue (characterized by avascularity, low expression of HLA antigens, and presence of immunomodulatory molecules), HLA-A, -B, and -DR matching can reduce the risk of rejection in high-risk cases (e.g., vascularized tissue, previous graft rejection, or active inflammation) (35–37). In such high-risk patients, ABO compatibility is also prioritized.

Small bowel transplantation, which is a relatively infrequent procedure, is indicated for patients with irreversible intestinal failure who are unable to maintain adequate nutrition and hydration through parenteral nutrition due to life-threatening complications such as liver failure, recurrent sepsis, or loss of central venous access. The small intestine is highly immunogenic and has one of the highest rates of acute rejection among all solid organ transplants (38). HLA-A, HLA-B, and, particularly, HLA-DR matching is ideal to improve graft survival and reduce the risk of rejection (39). However, due to the paucity of donors, practical application of HLA matching is limited, and immunosuppressive protocols play a pivotal role (38). These factors place patients at increased risk of developing immunosuppression-related complications, namely cellular rejection and AMR, infection, kidney disease, lymphoproliferative disorders, and GvHD.

ABO compatibility is usually mandatory, except for pediatric patients under 1 year old. Nevertheless, ABO-incompatible transplants could be feasible with the appropriate management of blood type antibodies and the use of adequate immunosuppression in the early period (40).

A first group of technologies focuses on refining histocompatibility assessment and improving donor–recipient matching at molecular and functional levels. On the one hand, RNA-based next-generation sequencing (NGS) and advanced bioinformatics pipelines now enable allele-specific HLA expression profiling, providing deeper insight into immune compatibility, informing donor selection more accurately, and improving predictive modelling for transplant outcomes. These techniques are especially relevant in HSCT (14).Similarly, high-resolution typing and eplet analysis have advanced compatibility beyond antigen-level matching. Algorithms such as HLA-Matchmaker, PIRCHE, and HLA-EMMA analyze amino acid polymorphisms and antigen-presenting peptide predictions to quantify mismatches more precisely, enabling clinicians to stratify risk at the molecular interface of HLA. These tools are particularly valuable in heart transplantation, where nuanced HLA compatibility influences graft survival and immunosuppression needs (18).

Additionally, artificial intelligence (AI) and machine learning (ML) have revolutionized donor matching and risk stratification. In HSCT, predictive models integrate HLA typing with clinical parameters such as patient comorbidities, disease stage, and immunogenetic factors to identify optimal donors (41). In kidney transplantation, AI and ML tools -including Chatbot- assist throughout the transplant process, from donor selection to postoperative monitoring (42). Other quantitative tools such as the Living Kidney Donor Profile Index (LKDPI) empirically compares potential living donors across multiple factors (viral serology, age, eplet matching) to more precisely characterize donor-recipient incompatibilities and improve long-term graft survival (43). In liver transplantation, ML models can be used to identify patients at high risk for developing GvHD and to predict graft failure (44–46). For lung transplantation, InsightTx employs XGBoost algorithms to predict outcomes based on ex vivo lung perfusion (EVLP) data (46, 47). Similarly, pancreas transplantation has benefited from Naive Bayesian Classifier and Support Vector Machine-based models to estimate rejection probability in simultaneous pancreas–kidney recipients (48). In corneal transplants, AI applications utilizing Optical Coherence Tomography (OCT) imaging have also demonstrated remarkable accuracy in evaluating graft rejection (49).

Finally, gene editing technologies also serve compatibility goals by directly modifying donor organs or cells to enhance compatibility at the genetic level. CRISPR/Cas9 tools allow targeted disruption of immunogenic loci (e.g., HLA, T cell receptor TCRα), insertion of safety or regulatory transgenes (e.g., suicide switches, cytokine modulators), and overexpression of immunotolerance-associated molecules (e.g., HLA-E, CD47). These interventions are being explored in heart and lung transplantation. In this field, Figueiredo and collaborators proposed silencing donor MHC molecules via shRNAs to reduce immunogenicity, while CRISPR/Cas technologies hold promise for generating universal blood type lungs (50–52).

While compatibility precision improves outcomes, donor scarcity remains a fundamental constraint, especially for time-sensitive organs. To address this, a spectrum of strategies has emerged to expand transplantable resources without compromising immunological feasibility.

In this context, xenotransplantation has made significant strides, particularly with porcine donors genetically modified to silence xenoantigens involved in hyperacute rejection (synthesizing α-1,3-galactosyltransferase, GGTA1; and β-1,4-N-acetyl-galactosaminyltransferase 2, B4GALNT2), and synthesizing N-glycolylneuraminic acid (CMAH)) and express human transgenic proteins that regulate immune response (CD47 and heme oxygenase 1), coagulation (human thrombomodulin, hTBM), and complement activation (CD39, CD46 and CD55). Proof-of-concept transplants of porcine kidney, heart, and liver into human recipients have shown early success, suggesting that compatibility can be manufactured, rather than matched (53–56).

Bioengineering and regenerative medicine approaches, such as tissue engineering and 3D bioprinting, are also expanding alternatives to traditional organ replacement while enabling the development of personalized therapies through the creation of functional organ substitutes. These strategies reduce dependence on donor availability and enable HLA-compatible solutions. Scaffolds from decellularized organs repopulated with human stem or allogeneic progenitor cells (such as in kidney and heart bioengineering) preserve the native extracellular matrix while removing immunogenic antigens, promoting regeneration and reducing immune rejection (57–60). Kidney and liver organoids mimicking native tissue architecture are also being developed to increase graft availability (61–63). Intestinal organoids derived from adult stem cells or iPSCs show promise for treating conditions like inflammatory bowel disease, celiac disease, and short bowel syndrome by restoring barrier integrity, modulating immune response, and supporting nutrient absorption. In mice, transplanted epithelial organoids integrate and promote mucosal healing, with some studies using hydrogels or decellularized scaffolds to engineer functional intestinal tissue (64–67). In pancreatic transplantation, alginate encapsulation of islets has been explored to reduce immune rejection, even without immunosuppression, in both allo- and xenotransplantation settings (68–72). In the kidney, 3D bioprinting technologies aim to recreate nephron-like structures for future renal replacement therapies (57, 73), while similar strategies in the liver and lung are used to fabricate transplantable hepatic tissue or airway structures, respectively (62, 74).

Lastly, ex vivo organ perfusion platforms such as normothermic machine perfusion (NMP) and EVLP extend the viability of marginal grafts and enable functional rejuvenation. These systems also act as delivery routes for immunomodulatory agents (e.g., MSCs) and gene vectors, thereby minimizing off-target effects and vector-induced inflammation and transforming preservation into a therapeutic window. Applied in kidney, heart, lung, and liver transplantation, perfusion technologies help bridge immunological gaps and optimize graft readiness (75–78).

When HLA or ABO compatibility cannot be strictly achieved, technological advances aim to neutralize immunological consequences and promote tolerance. Innovation in immunosuppressive regimens includes post-transplant cyclophosphamide (PTCy), costimulatory blockade, monoclonal antibodies targeting memory B and T cells, and targeted drug delivery. In HSCT, PTCy has gained prominence as a cost-effective method with strong GvHD prevention capacity, significantly expanding the use of haploidentical donors and redefining donor selection criteria (79). In lung, upregulation of interleukin-10 (IL-10) in models of acute rejection and CLAD has been shown to reduce inflammation and improve graft tolerance (80, 81). In intestinal transplantation, therapies targeting key inflammatory mediators, such as monoclonal antibodies against TNF-α and integrins, proteasome inhibitors and purine analogs, and modulation of the intestinal microbiome through selective antibiotics or probiotics reduce rejection while minimizing systemic toxicity (82).

Besides pharmacological approaches, cell-based immunomodulation is nowadays at the forefront. Regulatory T cells (Tregs) are increasingly used in HSC, kidney, liver, pancreas, and small intestine transplantation to prevent rejection and promote immune adaptation (82–87). Moreover, mesenchymal stromal cells (MSCs) exhibit immunosuppressive and anti-inflammatory properties, with therapeutic use spanning HSC, liver, lung (where a first-in-human study showed a slower decline in lung function in patients with advanced CLAD after MSCs infusion), and small intestine transplants (84, 86, 88–91). Additionally, regulatory dendritic cells have also shown promise in liver immunoregulation (92) and, recently, PRDM16-dependent APCs have been described to induce tolerance to gut antigens, offering new insights into developing therapeutic strategies for intestinal transplant tolerance (93). Chimerism-based strategies have been also tested, promoting immune adaptation through the co-transplantation of donor HSCs, as demonstrated in kidney and liver transplantation (94, 95). Finally, CAR-engineered immune cells, including CAR-T and CAR-NK, are under investigation in HSCT for their dual role in eliminating residual disease and modulating post-transplant immunity (83, 84, 96). AI-assisted monitoring complements these interventions. Tools analyzing gene expression profiles (e.g., AlloMap), donor cfDNA levels, and longitudinal patient data help detect early signs of rejection and guide immunosuppression tapering, thus allowing real-time adaptation and adjusting drug regimens dynamically to avoid over- or under-immunosuppression (42, 97–102).

These converging innovations indicate a shift from rigid antigen matching toward a functional and personalized approach to immunocompatibility. By integrating molecular precision, regenerative capacity, and predictive analytics, emerging technologies offer viable pathways to reconcile immunological complexity with therapeutic feasibility in modern transplantation.