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Update on Desensitization Strategies and Drugs on Hyperimmune Patients for Kidney Transplantation

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30 May 2023

Posted:

01 June 2023

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A peer-reviewed article of this preprint also exists.

Abstract
Abstract: Presence in a recipient of antibodies directed against donor specific antigens represent a major obstacle in transplanting such patients. Removal of these antibodies represents a challenge for physicians dealing with kidney transplantation. Several strategies, techniques and old and new drugs are to date used to desensitize these patients. Desensitization may occur before transplantation or at the time of transplantation or after transplantation according whether physicians deal with living or deceased donors. Different techniques may be used to reveal the presence of antibodies in the recipients; each technique has different sensitivity and specificity, different advantages and disadvantages. The target of the drugs used to desensitize are B cells, Plasma cells, the antibodies themselves and finally, the complement that is the final actor causing tissue disruption. If B cells are relatively easy to be targeted, more difficult are the plasma cell. Indeed, several new drugs are used in randomized trials also to defeat plasma cells. Antibodies may be removed rather easily, but often their removal is followed by a rebound. Complement is not easy to be defeated and new drugs are to date used to be successful in this action. However is to date possible to desensitize many patients and to obtain successful transplantation.
Keywords: 
Desensitization
;  
Donor specific antibodies
;  
HLA system
;  
antibodies identification
;  
B cells
;  
Plasma cells
;  
Complement
;  
New drugs
;  
Desensitization
;  
Donor specific antibodies
;  
HLA system
;  
B cells
;  
Plasma cells
;  
Complemennt
;  
New drugs
Subject: 
Medicine and Pharmacology  -   Transplantation

supplementary.docx (15.49KB )

Developing of sensitization

After the first alloantigen exposure, events such as pregnancies, transfusions, previous transplants or any contact with alloimmune antigens may generate a memory alloimmunity either cellular and serological [3,4].
When B cells bind to their cognate antigen, this initiates a migration toward the boundary between the B and T cell zones in lymphoid organs, where they compete for interactions with follicular helper cells. T follicular helper cells provide selection signals required for differentiation into Germinal Centers (GC) cells and antibody secreting cells. Additionally, it has been observed that after transplantation, circulating TFH expanded more significantly in patients who developed de novo anti HLA antibodies than in those who remained not sensitized [5]. An important role in generating alloimmune response is exerted by the long-lived plasma cells. After the generation of memory B cells, these transform in plasmablasts that are competent to home to survival niches. Plasmablasts migrate to bone marrow were generate long-lived plasma cells that migrate to survival niches under the effect of pathogen-associated molecular pattern (PAMP) [6,7]. Most of plasmablasts migrate to inflamed tissues, under the control of interferon gamma induced expression of CXC-chemokine receptor 3 (CXCR3) which binds CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11 [8,9].

Techniques to identify sensitization level and to stratify the risk

With different techniques is now possible to detect both the alloreactive serological memory and the alloreactive cellular memory in patients waiting for kidney transplantation so to stratifying the humoral and cellular risk of candidates to a solid organ transplantation [10].
The serological memory may be detected by complement dependent cytotoxicity [11], by flow cytometry [12], by solid phase assays as ELISA [13] and by bead-based assays as Luminex [14]. All these assays are shown on Table 1. Assays to evaluate alloreactive cellular memory are, among others, flow cytometry [15]. Elispot assay [16], solid phase assay [17], flow cytometry [18].
The immune-pathophysiology of DSA- mediated damages informs the prediction of antibody-mediated rejection and graft loss. The pathogenicity of DSA is routinely evaluated with their titer (MFI or dilution) or their ability to bind donor cells (by flow cytometry crossmatch). Ex vivo complement binding can be evaluated with the C1q and/or C3d assays. Analysis of complement fixing IgG subclasses or complement genetic variations, number of innate immune effectors and polymorphism of Fcγ receptors could all help to better stratify the risk of antibody-mediated rejection (AMR). Measurement of DSA affinity and glycosylation profile is not yet available. Finally, the characteristics of the target graft endothelial cell (level of expression of HLA molecules, stress-induced ligands or expression level of complement regulators or cytoprotective proteins) influence the pathogenicity of the DSA.
All the cited assays to detect the presence of HLA sensitization have different sensitivity and specificity. CDC has the lowest sensitivity that increases with the use of flow cytometry and a further increase is reached with the use of ELISA. The optimal sensitivity and sensibility is obtained with the use of single beads and with the use of complement binding. This fact allowed realizing the ENGAGE’s proposal for categorization of the humoral risk of solid organ transplant categories. The EuropeaN Guidelines for the mAnagement of Graft rEcipients (ENGAGE) [10] is an initiative from the European Society for Organ Transplantation that stratify the patient’s risk as follows:
(a)
If the patient has no DSA and no cellular memory, the transplant is possible with low risk for AMR;
(b)
If at the time of transplantation, there is absence of DSA, but there is a potential cellular memory against donor HLA, the transplant is possible with risk for AMR increased. The cellular memory is possible if there are historical DSA and/or pregnancy or previous transplant with repeat antigens. Other possibilities are transfusions with no information on blood donors.
(c)
If at the time of transplantation there are DSA, but with negative flow, the transplant is possible with risk for acute AMR and acceptable medium-term graft survival.
(d)
If at the time of transplantation there are DSA with positive flow and negative CDC, the transplant is possible, but there is a very high risk for acute AMR and accelerated chronic AMR.
(e)
If at the time of transplantation there are DSA with positive CDC, the transplant is not possible and there is the need of desensitization before proceeding with transplant.

Incidence of hyper immune patients and graft survival with desensitization

The number of hyper immune patients on the waiting list for kidney transplantation is increasing with the time. According Spanish data of 2020, sensitized patients with CDC-PRA >50% were from 10% to 15%, but the same patients evaluated by PRA-SAB (single antigen beads) increased to 40%- 50% [19].
In USA, according data from Montgomery et al. [20] more than 20.000 candidates for kidney transplant are sensitized. The authors conducted a study with desensitization on 211 sensitized patients and found that patient survival rates were 80.6% at 8 years from transplantation, as compared with 30.5% for patients that remained on waiting list. In a different multicenter study on the risk of incompatible kidney transplantation, Orandi et al. [21] compared the graft survival of patients with positive Luminex and negative flow cross match (PLNC) with positive flow and negative CDC (PFNC) and patients with positive CDC (PCC). All these patients were compared with compatible transplants. The hazard ratio (HR) for graft loss was 1.20 for PLNC, 1.65 for PFNC and 1.80 for PCC. The graft loss for the last two groups was significant (p<0.001). In a different study conducted in UK, Manook et al. [22] compared hyper immune patients desensitized before transplantation with compatible living donors (CLD) and compatible deceased donors (CDD). The 5-year graft survival rates were similar and the authors concluded that desensitization has no detrimental influence on patient survival rates, but does not offer a survival benefit.
Timing of desensitization
With respect to the day of transplantation, different timing and strategies may be applied.
In the case of living donation, an early pre-transplant desensitization is preferred until obtaining CDC or Flow X-match negative. Clearly different drugs at different dosage may be applied. In the case of deceased donors does not exist enough time and substantially two strategies may be applied. The immediate pre-transplant desensitization as used in Austria [23] or the post-transplant desensitization as used at the hospital Necker in Paris [24].
In the case of immediate pre-transplant desensitization, the Immunoadsorption (IA) is the preferred methods due to its ability to efficiently removal of IgG [25,26]. The IA treatment is immediately followed by the administration of antithymoglobulins (ATG) and/or anti-CD20 (rituximab). The graft survival rates at 3-year were similar in CDCXM positive and in CDCXM negative patients.
The protocol used at the hospital Necker in the case of deceased donors consisted in an induction therapy with ATG, which was started at the day of transplantation followed by high dose immunoglobulins (IVIg) that were repeated every 3 weeks for a total of 4 courses. At the end of plasmapheresis, 1 or 2 rituximab infusions were administered. The graft survival rates at 7-year post-transplantation were 80% even if lower to the graft survival of the control group.

Desensitization strategies and drugs

Summarizing what has been above descripted, 4 steps can be seen in the process leading to target tissue destruction. B cells are formed after antigen binding and B cells may act as antigen presentation and are precursor of Plasma cells. The second step is Plasma cells formation with consequent antibody formation. The antibodies that form immune complexes and activate the complement represent the third step. Finally, complement induces chemotaxis and lead to the target tissue destruction (Figure 1) [27].
Different drugs may act on the steps described. These drugs are well represented by the study of Jordan et al. [28] and their action is summarized in Table 2. In addition to the drugs described, there is an old, but efficient pleiotropic drug that may act at any stage. This are the IVIgs, generally given at the dose of 2g/kg for repeated times. The efficacy of IVIg, frequently associated with other drugs has been already described [24]. Vo et al. [29] conducted a study documenting the efficacy of IVIg in association with rituximab in inducing desensitization.

Drugs acting on B cells

Three main drugs act on B cell leading to their reduction and reducing their activity. Rituximab (RTX), ATG and Belimumab. In a study of Ramos et al. [30] conducted on 25 recipients of living donors needing desensitization, was evaluated the effectiveness of RTX, IVIg and ATG in reducing the number of splenic B cells and Plasma cells. The effect of multiple plasmapheresis plus low dose IVIg resulted enable in reducing naïve B cells, plasma cells and memory B cells. Adding RTX to the treatment was effective in reducing naïve B cells, without effect on memory B cells and plasma cells. Finally, adding ATG to the treatment led to reduction of memory B cells (CD27+), but again without any effect on plasma cells.
Belimumab inhibits growth and differentiation of B cells by blocking B lymphocyte stimulator (BAFF or BlyS). Indeed in normal conditions BAFF binds to the receptors, BAFF-R, B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI) leading to immature B cell survival and maturation, plasma cell survival and B cell survival and proliferation [31,32,33]. Belimumab is a complete human IgG1λ recombinant monoclonal antibody directed against BAFF and initially used for the treatment of systemic lupus erythematosus (SLE) [34].
Belimumab monotherapy was studied as a desensitization agent in kidney transplantation. Nevertheless, the study was terminated early for reported lack of efficacy (NCT01025193) [35].
Another phase 2 double-blinded randomized placebo-controlled trial of Belimumab plus standard of care is being examined for prevention of allograft rejection in renal transplant recipients (NCT01536379) [36]. Finally, the study of Banham et al. [37] in an experimental medicine, randomized, placebo controlled trial documented the Belimumab efficacy. The concentration of activated memory B cells decreased from week 21 to 28 of the treatment and the addition of Belimumab to standard of care immunosuppression significantly reduced de novo IgG antibody.

Drugs acting on Plasma cells

The second step is represented by plasma cells both short and long living that are the principal responsible of antibody production. FcγRIIb that is an inhibitory receptor for the Fc portion of IgG controls the persistence and apoptosis of bone marrow plasma cells. It is expressed on B cells [38]. The crosslinking of FcγIIb on naïve B cells May induce apoptosis of B cells [39,40]. Another study documented that FcγIIb controls bone marrow plasma cells and if crosslinked induces plasma cells apoptosis [41].
A drug efficient in acting against Plasma cells is proteasome inhibitor. It is well documented that after proteasome inhibitor administration as Bortezomib there is a reduction in number of antigen-specific plasma cells in candidates to living donor kidney transplantation [42]. Bortezomib was able to reduce serum levels of DSA in patients, which were not affected by IVIg or RTX. In addition, Bortezomib reduced the number of antigen-specific plasma cells, without decreasing the total number of plasma cells. In a different study [43], proteasome inhibition caused apoptosis of normal human plasma cells preventing alloantibody production. Treatment with Bortezomib resulted in a significant increase in the percentage of apoptotic cells, while RTX, ATG and IVIg had no effect.
However, in different well-conducted studies, Bortezomib did not confirm its efficacy with respect to other treatments in reducing DSA after transplantation in sensitized patients. In particular, Ejaz et al. [44] divided their patients in four groups. One group received ATG alone, a second group received ATG + RTX, a third group received ATG + Bortezomib, a fourth group received ATG + RTX + Bortezomib. The results in their capacity to reduce DSA post-transplant was similar for all groups as shown in Table 3. Similarly, Eskandary et al. [45] conducted the study BORTEJECT. The study was a randomized, placebo-controlled trial to investigate the effect of Bortezomib on the course of late ABMR. Bortezomib given as single agent did not obtained improvement of the course of late rejection. These studies called for new agents acting on plasma cells. Carfilzomib is a second-generation irreversible proteasome inhibitor. It is an expoxyketone nonboronated molecule that proven to be effective and with reduced toxicity in the treatment of patients with multiple myeloma [46]. In a randomized clinical trial (NCT02442648) [47] the B-Cell Targeted Desensitization with Carfilzomib for Preformed Anti-HLA Antibodies in Patients Awaiting Kidney Transplantation has been evaluated. A study from Tremblay et al. evaluated the prospective [48], iterative, adaptive trial of carfilzomib-based desensitization. The study documented that HLA antibodies were substantially reduced in the group treated with carfilzomib alone.
A different strategy to an effective desensitization is by the use of the Interleukin-6 receptor specific humanized monoclonal antibody, better known as Tocilizumab. Indeed IL-6 promotes B cells differentiation to plasma cells and induces Th17 cells. Vo et al. [49] used Tocilizumab in addition to IVIg in patients difficult to be desensitized. Tocilizumab reduced DSA strength and numbers at transplant and 12 months after transplantation. Protocol biopsies showed no evidence of antibody-mediated rejection or transplant glomerulopathy. In the study, after effective desensitization and transplantation, patients subsequently received IVIg once and Tocilizumab monthly for 6 months. The number of patients is low and the authors themselves highlight that larger controlled studies are needed. Later on, Doberer et al. [50] verified the efficacy of a different anti-IL-6 antibody, Clazakizumab, on late ABMR. Clazakizumab is a humanized monoclonal IgG1 antibody. With respect to Tocilizumab has a higher affinity for IL-6 and a longer half-life, as documented by studies on psoriatic arthritis [51].
The receptor specific for plasma cells is CD38. Daratumumab is a human immunoglobulin IgGk1 monoclonal antibody that target the CD38 surface antigen on plasma cells. Daratumumab has been used successfully in treating multiple myeloma and AL amyloidosis. Moreover, unlike Bortezomib, Daratumumab targets nonmalignant plasma cells. Hence its efficacy in desensitization and in treatment of ABMR [52,53].
Daratumumab has been successfully used in sensitized kidney transplantation in a nonhuman primate model [54]. Recently [55], four cases of transplant patients desensitized and treated with Daratumumab for AMBR have been reported [54,56,57,58] (Table 4).

Drugs acting on antibodies

Plasma cells produce antibodies that are dangerous because may form immune complexes and may activate the complement cascade.
Removal of DSA antibodies is mandatory in the different methods of desensitization or of treating ABMR.
The use of IVIg has been already treated and represents an important strategy for desensitization as used at the Hospital Necker [24].
A pioneer study suggested that polyclonal Ig could be efficient at decreasing anti-HLA antibodies [59]. Later on, a randomized trial (NIH IG02) compared pre-transplant administration of polyclonal Ig with placebo in highly sensitized patients [60]. Unfortunately, the NIH IG02 documented that, even if the transplantation rate was higher in the IVIg group, there was only a mild and transient effect on PRA. This fact led to a higher incidence of ABMR in the IVIg treatment group.
IVIg seems to be more efficient when associated with mechanical antibody removal as obtained with plasmapheresis. Montgomery et al. [61] conducted a study in sensitized living-donor kidney transplant recipients. Desensitization was conducted with a combination of plasmapheresis (PE) and subministration of IVIg. Post-transplant ABMR occurred as effect of antibody rebound after contact with allogenic antigens. The ABMR was easier controlled with new cycle of PE and low dose IVIg. As recommended by the already mentioned desensitization protocol [24], it is essential that the administration of IVIg always follow the PE to avoid the removal of Ig with the PE treatment.
According the European Guideline for the management of kidney transplant patients with HLA antibodies both PE and Immunoadsorption are effective [62]. Their efficacy is higher when associated with IVIg and RTX. IA is more selective and is the preferred method by some authors, in particular in the preparation of AB0 incompatible kidney transplantation [63,64,65].
A different method to neutralize antibodies is the use of the IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves intact IgG. Intact human IgG is cleaved by IdeS in two steps. The first step results in a single cleavage of the IgG molecule in which one heavy chain remains intact. The second step generates a fully cleaved molecule that cannot mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cytotoxicity (ADCC) by means of Fcγ receptors [66,67]. A study from Jordan et al. [68] represents the first pilot study that combines 2 phase 1-2 trials undertaken independently. Overall, 25 highly immunized recipients were treated: 14 in the USA, 11 in Sweden. 1 shot of IdeS 4 to 6 hours before transplantation. IdeS is extremely potent at cleaving circulating IgG, but the effect may be transient. The extent and frequency of DSA rebound after transplantation highly varied between the Swedish and the American arms of the study. Indeed, in the Swedish group DSA remained undetectable up to 14 days from transplantation, with a subsequent rebound. In the USA patients, the rebound was very low. This possibly is the effect of the use of IVIg plus RTX before and after transplantation [69,70]

Drugs acting on complement

The fourth and final step to be targeted is the complement that favors chemotaxis and lead to tissue destruction. It has been documented that terminal complement inhibition decreases ABMR rates in sensitized renal transplant recipients [71]. In this study, complement inhibition and desensitization was made with the use of the anti C5 eculizimab. Eculizumab was given at the dose of 1200 mg immediately prior to transplantation, 600 mg on postoperative day 1 and 600 mg weekly for 4 weeks. Eculizumab was than discontinued if DSA had significantly decreased or continued until B flow crossmatch channel shift was < 200. Graft survival and ABMR rates were significantly lower in the eculizumab group with respect to control group. However, looking at the outcomes beyond 1 year, the incidence of transplant glomerulopathy did not differ in the two groups [72]. In a more recent study, Marks et al. [73] conducted a randomized trial on the safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization. There was a lower rate of ABMR in the eculizumab arm compared to the arm with standard of care. However, at 3 years there was a similar graft survival.
A different and new way of targeting complement is to target the enzymes of the initiating complement cascade [74]. This can be obtained by the use of the serine protease inhibitor (C1INH) [75]. There are two forms of C1INH: the ultra-pure derived C1INH and the full-length recombinant C1INH. This drug has its advantage and its drawback. Advantage is its knowledge for the fact of being the standard of care for hereditary angioedema [76,77]. Additionally, plasma derived molecules are not immunogenic and it has a broad effect on classical and lectin pathways. Main drawback is the lack of specificity. Indeed, C1INH also controls Mannose-binding lectin-associated serine protease (MASP) and protease in the coagulation and kinin systems. Though being new and promising, to date C1INH is only used in preliminary results of ABMR treatment, but it is not yet used as prophylaxis.

Author Contributions

M.S. designed the study, performed the last revision. Collected data from literature and wrote the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The Author does not have any conflict of interest in relation to the manuscript.

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Preprints 75196 g001
Figure 1. targeting different cells or functions.
Figure 1. targeting different cells or functions.
Preprints 75196 g001
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