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Immunosuppression in Sensitized Patients
Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients.
Immunosuppressive strategies for sensitized patients are largely borrowed from those used in non-sensitized patients. However, variability in outcomes reveals the insufficiency of current immunosuppressive regimens in sensitized patients. Sensitized patients with a negative crossmatch (no donor-specific antibody) showed comparable graft survival to non-sensitized patients in the current organ allocation system  even though these patients might have individual center-driven immunosuppressive regimens which are different from non-sensitized patients (i.e., thymoglobulin with higher Tac trough level, etc.). However, immunologically high-risk transplants occurring in sensitized patients, particularly for crossmatch positive, incompatible transplants, require enhanced immunosuppression. Innovation in this field has largely focused on ‘desensitization’ prior to transplantation, or early post-transplant therapies to reduce the risks of acute antibody-mediated rejection (AMR) ; however, there has been little examination of the optimal maintenance regimen post-transplant. Furthermore, even with currently available desensitization therapies, both acute AMR and acute cellular rejection (ACR) rates were significantly higher in sensitized/desensitized patients compared to non-sensitized patients . Recently, changes in deceased donor allocation in the US in particular , as well as improvements to living kidney donor sharing schemes , have demonstrated that fewer sensitized patients require the need for cross-match positive living transplantation . Nonetheless, patients with pretransplant or de novo donor-specific antibody (DSA) are at greater risk of graft rejection.
2. Choice of Induction Therapy in Sensitized Kidney Transplant Recipients
Thymoglobulin, or rATG, is a polyclonal gamma immunoglobulin and the preferred choice in sensitized patients at high risk for acute rejection or delayed graft function . rATG targets T cells via antibody dependent cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), but it also depletes B cells and plasma cells since thymus also contains these cell populations. In moderately sensitized patients (positive DSA and negative flow crossmatch), induction with ATG resulted in reduced occurrence of de novo DSA (dnDSA) and AMR compared to basiliximab . In simultaneous heart and kidney transplants, sensitized patients (with PRA > 10%) treated with rATG induction had lower mortality .
Alemtuzumab is a depleting anti-CD52 antibody that targets T and B cells resulting in lymphocyte depletion and prolonged immunosuppression . Low-dose alemtuzumab is used as an induction agent in sensitized patients undergoing kidney transplantation and, when combined with triple maintenance immunosuppression, is well tolerated and has shown favorable patient and allograft outcomes (death-censored graft survival: 79.2%) . A prospective study found that the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab when compared with basiliximab, but among high-risk patients, there was no significant difference between alemtuzumab and rATG . However, alemtuzumab is associated with prolonged lymphocyte depletion  and increased rates of infection .
Rituximab is an anti-CD20 monoclonal antibody that targets B cells, suppresses preformed alloantibodies and reduces peripheral B lymphocytes prior to transplantation . A retrospective study of highly sensitized kidney transplant recipients (XM-positive or DSA positive) treated with IVIG and rituximab induction therapy found increased rates of AMR in sensitized recipients compared to low-risk recipients, but similar long-term patient or graft survival at 6 year follow-up .
3. Choice of Maintenance Immunosuppression in Sensitized Patients
3.1. Triple Immunosuppression
Maintenance immunosuppressive therapy prevents acute rejection and increases allograft survival following kidney transplantation. The standard maintenance regimen varies by center or clinician preference, but the KDIGO Transplant Work Group guideline recommendations include triple therapy immunosuppression consisting of a calcineurin-inhibitor (CNI), such as tacrolimus, an antimetabolite, such as mycophenolate mofetil (MMF), and a glucocorticoid, such as oral prednisone, in kidney transplant recipients . Tacrolimus inhibits activation of T lymphocytes by binding to an intracellular protein, FKBP-12, and inhibiting calcineurin while MMF inhibits T and B cell proliferation. It has been shown that CNIs (cyclosporine and tacrolimus) inhibit antibody production in T and B cell cultures but fail to inhibit immunoglobulin (Ig) production when B cells are cultured with primed T cells . According to the most recent Scientific Registry of Transplant Recipients (SRTR) registry data, over 60% of patients are discharged from the hospital on tacrolimus, MMF, and prednisone triple therapy due to its success as a maintenance immunosuppressive regimen .
3.2. Limited Efficacy of Standard Maintenance Immunosuppression in Sensitized Patients
Graft function was similar between groups at 1 year follow-up with no graft loss, and both groups were treated with thymoglobulin induction and standard maintenance triple therapy . A study in which all patients were maintained on standard triple therapy found an increased incidence of acute AMR in patients with pretransplant DSA than those without (41.7% vs. 1.6%, p < 0.001) and that higher levels of pretransplant DSA had a detrimental effect on 5 year graft survival . These studies highlight the limitations of standard triple maintenance immunosuppressive therapy and the need for different therapeutic regimens in the sensitized, DSA positive, CDC-crossmatch negative patient population, particularly in light of the experimental evidence highlighted regarding the inability of CNI to prevent antibody production during cognate T–B cell interactions .
3.3. Replacing Tacrolimus
The mammalian target of rapamycin (mTOR) controls the T cell response (activation and proliferation) and is a valuable immunosuppressant in clinical transplantation. mTOR inhibitors, such as rapamycin (sirolimus) and everolimus, promote the differentiation and function of various helper T cells and suppress the differentiation of memory CD8+ T cells . Furthermore, unlike CNIs, mTOR inhibitors are able to prevent Ig production from B cells when cultured with primed T cells, which suggests their direct impact on B cells . Rapamycin has also shown its superiority over tacrolimus with respect to inhibiting B cell to plasma-cell differentiation . In mice sensitized by prior skin graft, preoperative rapamycin increased the expression of regulatory T cells, but did not prolong the survival of mice after cardiac allotransplantation . In donor skin-sensitized mice, those with mTOR deletion in T cells had longer mean survival time (MST 19.5 days) versus wild-type recipients (MST 5.4 days) . Mice sensitized by skin transplant and treated with rapamycin induction therapy were found to have altered frequencies of splenic and intragraft neutrophils, macrophages, and natural killer (NK) cells .
4. Newly Available Agents for Sensitized Patients
4.1. Costimulation Blockade
Belatacept, a CTLA4-Ig fusion protein that binds to cluster of differentiation (CD) 80 and CD86 receptors on antigen presenting cells (APC), prevents binding to CD28 on T cells, thereby reducing the T cell–dependent immune response . Belatacept has been shown to selectively reduce the humoral response in sensitized, maximally HLA-mismatched non-human primates (NHPs) by suppressing the peripheral and germinal center follicular helper T cell (Tfh) response . Translational studies in highly sensitized NHPs found that desensitization with belatacept in combination with bortezomib or carfilzomib therapy led to significantly reduced AMR, DSA, and plasma cells leading to prolonged graft survival, although it should be noted that these animals received tacrolimus-based triple therapy as maintenance . Preliminary studies in animals receiving belatacept in addition to triple therapy indicate a further prolongation of survival, even in a highly sensitized NHP model .
The CD40/CD154 pathway is important for activating T cell differentiation and B cell isotype switching and was found to be important in both the humoral and cell-mediated immunologic response pathways . CD4+ helper T cells are mandatory for generating both naïve and memory DSA responses . Thus, targeting helper T cells in maintenance therapy may lead to decreased AMR and prolonged allograft survival in kidney transplant recipients. Much of the existing evidence is in large animal models as clinical studies blocking the CD40/CD154 pathway have been halted due to the development of thromboembolic complications and direct platelet activation . Thromboembolic complications were found to be primarily due to blocking interactions with CD154, which is important for thrombus stability . However, similar events were not observed in antibodies targeting CD40 , so this may be a more promising therapeutic target. A novel blocking, non-depleting Fc-silent anti-CD40 mAb, iscalimab (CFZ533), has been found to prolong renal allograft survival in NHP in the absence of B cell depletion with no evidence of thromboembolic events .
4.2. Adjuvant Therapies
4.2.1. Targeting IL-6 or IL-6R
Interleukin (IL)-6 is a pleiotropic cytokine involved in a variety of pathways regulating immune responses, with an important role in the induction of follicular helper T cells which stimulate B cells to differentiate into memory B cells and IgG-secreting plasma cells . The IL-6 receptor (IL-6R) exists as a membrane-bound protein, expressed mostly on hepatocytes and immune cells, and a soluble protein that can bind IL-6 and transmembrane gp130, termed trans-signaling, on nearly all cell types . Interactions between IL-6 and IL-6R lead to the activation of transmembrane protein gp130, eliciting signals to downstream JAK and MAPK pathways and the subsequent activation of inflammatory genes . IL-6 is a proinflammatory cytokine that plays a pathologic role in chronic immune disorders, cancer, and transplant rejection . IL-6 also promotes Th17 differentiation and inhibits Treg differentiation, suggesting targeting IL-6/IL-6R may have clinical applications in treating autoimmune disease and organ rejection .
4.2.3. Targeting PC
5. Concluding Remarks
The entry is from 10.3390/jcm10163656
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