Introduction
Despite significant advances in the field of transplantation in the past two decades, current clinically available therapeutic options for immunomodulation remain fairly limited. The advent of calcineurin inhibitor–based immunosuppression has led to significant success in improving short-term graft survival; however, improvements in long-term graft survival have stalled. Solid organ transplantation provides a unique opportunity for immunomodulation of both the donor organ prior to implantation and the recipient post transplantation. Furthermore, therapies beyond targeting the adaptive immune system have the potential to ameliorate ischemic injury to the allograft and halt its aging process, augment its repair, and promote recipient immune tolerance. Other recent advances include expanding the donor pool by reducing organ discard, and bioengineering and genetically modifying organs from other species to generate transplantable organs. Therapies discussed here will likely be most impactful if individualized on the basis of specific donor and recipient considerations.
RECIPIENT IMMUNOMODULATION
Novel Pharmacological Immunosuppressive Therapies: Beyond Calcineurin Inhibitors
While calcineurin inhibitors have significantly reduced acute rejection rates and improved 1-year allograft survival, their impact on long-term allograft survival remains limited. This is due to adverse metabolic effects such as nephrotoxicity, post-transplant diabetes, and dyslipidemia, which can lead to allograft injury. As a result, there is an urgent need for alternative immunosuppressive therapies that do not rely on calcineurin inhibitors.
Costimulation blockade
Costimulation blockade has emerged as a promising strategy in immunosuppressive therapy. T cell activation requires two signals: antigen recognition (signal 1) and costimulation (signal 2). Blocking costimulatory pathways like CD28-B7 and CD40L-CD40 can inhibit T cell activation. For instance, CTLA-4-Ig (belatacept) blocks the CD28-B7 interaction and mimics CTLA-4 signaling, reducing T cell activation and improving long-term kidney allograft outcomes. Belatacept has shown better kidney function and fewer side effects compared to cyclosporine, despite a higher risk of early acute rejection. Similarly, CD40-CD40L blockade has shown significant success in preclinical models, although earlier versions of anti-CD40L agents were linked to thromboembolic complications. Newer agents without these risks are under development.
Desensitization
Desensitization therapies aim to address the issue of preformed anti-HLA antibodies, which limit access to donor organs. Early therapies like intravenous immunoglobulin and plasmapheresis had limited success. B cell depletion using anti-CD20 (rituximab) has shown moderate effectiveness, while therapies targeting plasma cells, such as anti-CD38 and proteasome inhibitors, provide only transient reductions in antibody levels. Imlifidase, an enzyme that cleaves IgG, offers rapid DSA reduction, making it a useful tool in acute settings when combined with longer-term treatments to prevent antibody-mediated rejection (ABMR).
Therapies for ABMR
Antibody-mediated rejection (ABMR), driven by donor-specific antibodies (DSAs), poses a significant threat to allograft survival. While terminal complement inhibitors like eculizumab reduce DSAs, they fail to improve long-term graft outcomes. Anti-IL-6 therapy has shown promise by reducing inflammation, fibrosis, and DSA levels, while stabilizing kidney function. Beyond T and B cells, natural killer (NK) cells have emerged as contributors to ABMR through microvascular damage. Future therapies targeting NK cells may revolutionize ABMR treatment by addressing this previously overlooked pathway.
Cellular Immunomodulatory Therapies
Peripheral Modulation via Single Suppressor Cell Population Infusion
Infusing suppressor cell populations offers a targeted approach to dampen transplant immune responses. These cells, such as regulatory T cells (Tregs), exert immunosuppression through both antigen-specific and nonspecific mechanisms. Tregs, the most studied population, suppress effector T cells and antigen-presenting cells (APCs), while promoting regulatory B cells and myeloid-derived suppressor cells. Other suppressor cells under clinical investigation include regulatory macrophages, tolerogenic dendritic cells (DCtols), and mesenchymal stromal cells (MSCs).
Despite promising results, several challenges hinder their clinical application. First, determining whether donor or recipient cells should be used remains unresolved. Recipient cells are more accessible post-transplantation but may be affected by ongoing immunosuppression. In contrast, donor cells are harder to obtain, especially from deceased donors, and risk triggering alloimmunity. Second, identifying the optimal cell dose is complex, varying with cell type and individual patient responses. For instance, donor-specific Tregs appear more effective than polyclonal Tregs, prompting efforts to expand these cells ex vivo. However, extensive manipulation increases the need for rigorous quality control. Finally, ensuring that infused cells function as intended and remain effective over time is critical. Current understanding, primarily based on preclinical data, suggests these therapies may reduce but not entirely eliminate alloimmune responses, necessitating complementary treatments for achieving tolerance.
Peripheral Modulation via Multiple Suppressor Cell Populations
Combining multiple suppressor cell populations may yield synergistic immunosuppressive effects. However, logistical challenges make ex vivo generation of such combinations impractical. An alternative approach involves engaging these populations in vivo, such as through the infusion of donor apoptotic cells. Apoptotic cell clearance is a natural, non-inflammatory process that can mobilize regulatory macrophages, Tregs, DCtols, and myeloid-derived suppressor cells, collectively establishing immunoregulation.
Research has demonstrated that treating cells with ethylene carbodiimide (ECDI) induces rapid apoptosis post-injection, promoting donor-specific tolerance. These ECDI-treated cells act as donor “decoys,” reinforcing immune inhibition when administered periodically. Importantly, this method avoids sensitization, a common issue with live donor cell infusions. Preclinical studies, including rodent and non-human primate models, support this strategy as a robust peripheral tolerance mechanism. However, external factors like infections could potentially disrupt this balance, highlighting the need for ongoing evaluation.
Central Modulation Through Donor-Recipient Bone Marrow Chimera
Central deletional tolerance, achieved by inducing a bone marrow (BM) chimera, represents a highly robust transplantation tolerance strategy. This concept was illustrated in cases where kidney and BM transplants from the same donor led to immunosuppression-free kidney transplantation in patients with multiple myeloma. The challenge lies in applying this approach without the underlying need for BM transplantation to treat malignancies.
Two major obstacles are minimizing recipient preconditioning while promoting effective donor BM engraftment and eliminating the risk of graft-versus-host disease (GVHD). Advances such as facilitating cells, which include various suppressor populations, have shown promise in supporting BM engraftment, though GVHD risk persists. Additionally, co-transplantation of thymic tissues with solid organs or generating chimeric thymus using induced pluripotent stem cells (iPSCs) offer potential avenues for establishing central tolerance. However, key questions regarding native thymus involvement and chimeric thymus parameters remain. These developments may eventually enable donor-specific central tolerance without GVHD risks.
Noncellular Immunomodulatory Therapies
Extracellular Vesicles (EVs)
EVs are lipid bilayer particles naturally released from nearly all cells, carrying bioactive cargo for cell-cell communication. Their function varies based on cellular origin. For instance, EVs from donor dendritic cells (DCs) can trigger immune responses via semidirect recognition, while EVs from neutrophils, macrophages, or MSCs exhibit immunomodulatory and reparative effects. Neutrophil EVs suppress inflammation by inhibiting DC and macrophage activation and expanding Tregs. MSC-derived EVs aid tissue repair by carrying factors that promote regeneration in organs like kidneys, lungs, and hearts. Engineered EVs can enhance therapeutic potential, and MSC-EVs are currently under clinical investigation for transplant rejection therapy.
Nanotechnology
Nanotechnology offers innovative solutions for immunomodulation by enabling controlled drug delivery. Nanochannel membranes in implantable devices allow sustained drug release, while liposome-encapsulated drugs like rapamycin enhance pharmacokinetics. Nanoparticles (NPs) can be used to target immunosuppressive agents directly to grafts or lymphoid tissues, improving efficacy and reducing systemic exposure. For example, MECA79-coated NPs loaded with tacrolimus improve graft survival in heart transplant models. Similarly, NPs delivering anti-CD40L enhance transplant tolerance. Donor antigen-loaded NPs can also replace apoptotic cell infusions, promoting regulatory cell expansion and tolerance induction in experimental models.
DONOR OR DONOR ORGAN IMMUNOMODULATION
Ex vivo Machine Perfusion
Traditional static cold storage (SCS) has long been used for organ preservation, but it has limitations, especially for high-risk donor organs. Ex vivo machine perfusion (MP) is a newer method that uses continuous circulation of perfusates at different temperatures. Hypothermic machine perfusion (HMP) improves graft survival and reduces complications like delayed graft function. In liver transplants, HMP lowers inflammatory markers, indicating better oxygenation and reduced immune activation. Normothermic machine perfusion (NMP) allows near-physiological preservation by maintaining cellular metabolism, enabling organ viability assessment, and supporting reconditioning therapies like gene modulation and immune cell modulation.
Senolytics
Aging and chronic diseases lead to the accumulation of senescent cells, which release inflammatory factors through the senescence-associated secretory phenotype (SASP). This contributes to “inflamm-aging,” affecting both transplant donors and recipients. Senolytic drugs like ATM kinase inhibitors and JAK inhibitors can mitigate these effects by targeting SASP. In transplant settings, drugs like dasatinib and quercetin have shown promise in reducing age-related inflammation and prolonging organ survival by eliminating senescent cells. Senolytics present a valuable opportunity to expand the use of older donor organs, reducing organ discard rates.
Engineering New Organs
Approaches to Engineering New Organs
Tissue Engineering
Tissue engineering offers promising solutions for flat tissue transplants like skin and bladder. Advances such as “organ-on-a-chip,” organoids, and scaffold technologies have enabled the development of tissue-level constructs. Engineered tissues can be designed to match the recipient’s genetics or reduce immunogenicity through biomodification or encapsulation. Techniques like decellularizing donor organs and repopulating them with patient-derived cells show potential, as seen in functional rat organ models. However, more progress is needed before fully transplantable organs become a reality.
Gene Editing for Xenotransplantation
Xenotransplantation, using genetically modified pigs, addresses organ shortages by overcoming human immune barriers. Innovations like GGTA1 gene knockout and insertion of human complement regulatory proteins (e.g., CD46, CD55, CD59) have significantly reduced hyperacute and delayed rejection in pig-to-human transplants. Advances in gene editing have enabled multiple genetic modifications, leading to breakthroughs such as successful pig heart and kidney transplants in humans. These developments mark a turning point for xenotransplantation.
Summary
The future of organ transplantation is promising, with advances in immunosuppression, cell-based therapies, and organ engineering. These innovations aim to address organ shortages and reduce complications from lifelong immunosuppression. A personalized approach, tailored to individual donor and recipient needs, will be essential for optimizing transplant outcomes.
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