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Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?

Sicard, Antoine MD, PhD1; Kanitakis, Jean MD2; Dubois, Valérie MD3; Morelon, Emmanuel MD, PhD1,4,5; Thaunat, Olivier MD, PhD1,4,5

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doi: 10.1097/TP.0000000000003164
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Abstract

INTRODUCTION

Since the first successful transplantation performed in 1954, the management of solid organ transplant (SOT) recipients has considerably evolved. Sixty-five years of clinical experience have witnessed spectacular progress, ranging from the development of novel surgical procedures to the discovery of key immunosuppressive drugs. Major advances in transplant immunology have allowed for the identification of the mechanisms that govern allograft rejection. Importantly, humoral alloreactivity and antibody-mediated rejection (AMR) have progressively emerged as the main cause of allograft loss in many different types of organ transplant recipients.1-6

The first human vascularized composite allotransplantation (VCA) was performed in 1998,7 44 y after the first kidney transplantation. Since then, <150 patients have received VCA worldwide, which contrasts with the hundreds of thousands of SOT procedures that have been performed to date. The lack of clinical data results in uncertainties concerning the management of VCA patients. In particular, the clinical significance of humoral alloreactivity in the setting of VCA transplantation is still a matter of debate.8 On the one hand, the experience in SOT incites us to consider donor-specific humoral alloreactivity in VCA recipients with the utmost caution. On the other hand, a direct extrapolation of the rules established in SOT recipients might not be correct, given the singularities of VCA.9

In this overview, we first review important basic concepts concerning humoral alloimmunity in solid organ transplantation. We then evaluate which of these concepts are applicable, and how they can be adapted to help in the evaluation and management of humoral alloreactivity in VCA recipients

HUMORAL ALLOIMMUNITY IN ORGAN TRANSPLANTATION

Since the discovery of rejection, transplant immunologists have aimed to determine the respective role played by T and B cells in this process.

Experimental and Clinical Recognition of the Pathogenicity of Donor-specific Antibodies

Two experimental observations have initially highlighted the major role played by T cells in allograft rejection and overshadowed the role played by B cells and alloantibodies. First, skin allografts were not rejected in animals lacking T cells.10 Second, adoptive transfer of T cells, but not alloantibodies, was sufficient to restore the rejection of skin allografts in immunodeficient recipients.10 However, some clinical evidence that humoral alloimmunity was deleterious was also obtained. The deleterious role played by anti-A and anti-B antibodies was rapidly identified and ABO compatibility was quickly recommended. In addition, the presence of preformed circulating cytotoxic donor-specific antibodies (DSAs) was associated with “hyperacute rejection” in kidney transplant recipients,11 and the generation of de novo DSAs after transplantation was associated with poor outcomes and histologic vascular lesions, a process called “vascular rejection.”12 How was it possible to reconcile the clinical observations demonstrating a deleterious role of alloantibodies and the experimental data showing resistance of skin grafts to passive transfer of alloantibodies? Medawar and other transplant immunologists have suggested that observations made using skin grafts might not apply to organ transplants. Confirming the assumption made by the pioneers, Russel et al13 showed that the passive transfer of alloantibodies to immunodeficient murine heart allograft recipients led to the development of obstructive coronary lesions, providing the first experimental confirmation of the clinical observations. We then understood that the pathogenicity of alloantibodies was determined by the origin of allograft vessels. In contrast with grafted skins whose vascularization develops from the recipient, the vascularization of organ transplants is ensured by vessels from donor origin. In the skin graft settings, DSAs, which are large molecules mainly sequestrated in the circulation, cannot access their target alloantigens.14 In contrast, in organ transplantation settings, circulating DSAs are in direct contact with allogenic donor endothelial cells, which explains the susceptibility of organ transplants to alloantibodies.14 Several clinical studies further highlighted the deleterious impact of preformed or de novo DSA in SOT recipients, and AMR was progressively acknowledged as a main cause of allograft loss in kidney, heart, pancreas, or lung transplant recipients.1-6,15

Detection of Donor-specific Humoral Alloreactivity and Related Damages

The collective awareness of the clinical significance of AMR led the transplant community to seek diagnostic criteria of AMR. Naturally, the classical pathophysiologic sequence of AMR served as a basis (Figure 1). The sequence starts with the generation of antibodies directed against donor-specific HLA molecules (DSAs). Circulating DSAs bind to mismatched HLA molecules expressed by graft endothelium, which leads to allograft destruction by endothelial cell activation, complement activation, and recruitment of innate immune effectors through Fc gamma receptors.16 Coherently, 3 cardinal criteria of AMR diagnosis were initially defined in 2005 by the Banff Conference on Allograft Pathology: (1) presence of circulating DSAs, (2) positive staining for complement in peritubular capillaries (C4d staining, used as a footprint for complement activation), and (3) presence of microvascular inflammation (glomerular or peritubular capillaries score >0).17 This classification prevailed during several years before the transplant community questioned the diagnostic criteria. During that period, a high proportion of patients with DSAs and microvascular inflammation on graft biopsies were not considered as patients with AMR because C4d staining was negative. Clinical observations together with both transcriptomic analysis showing evidence of antibody-mediated damages despite lack of C4d staining18 and experimental data demonstrating that DSAs can trigger vascular lesions without complement participation19 led tardively to the recognition of C4d-negative AMR20 (Figure 1). During the same period, it also became clear that patients could display histologic lesions suggestive of AMR, that is, microvascular inflammation and/or complement activation, in the absence of circulating anti-HLA DSA21 (Figure 1). This observation is mainly explained by the fact that the current testing methods do not allow for detection of all harmful antibodies due to technical limitations, but also because these methods focus on the detection of anti-HLA antibodies alone. There is evidence that DSAs can also be directed against non-HLA targets, including polymorphic minor histocompatibility antigens22 or nonpolymorphic autoantigens after a breakdown of B cell tolerance.23,24 Studies have demonstrated that these “non-HLA” antibodies can be pathogenic, especially when the target is expressed on the endothelial cell surface,25,26 such as antiangiotensin II type-1 receptor antibodies.27 In sum, the initial vision of AMR has considerably evolved during the last 15 y along with technical advances, experimental findings, and clinical hindsight. There is no doubt that AMR can have several distinct phenotypes, which should be taken into account when establishing diagnosis criteria for AMR (Figure 1).

FIGURE 1.
FIGURE 1.:
How experience in SOT could help defining AMR in VCA. The successive steps identified in the pathophysiology of AMR are shown on the left. The central part of the figure presents the lessons learned from our experience with transplanting “conventional” solid organs. The possible implications for VCA are shown on the right. AMR, antibody-mediated rejection; DSA, donor-specific antibody; SOT, solid organ transplant; VCA, vascularized composite allotransplantation.

Management of Humoral Alloreactivity

Given the poor prognosis of AMR, preventing DSA appearance is the first priority. The choice of the immunosuppressive protocol is primarily guided by its potential to prevent DSA generation (for recent review, see Thaunat et al28). Experimental and clinical studies have suggested that induction with thymoglobulin decreased the risk of DSA appearance, but the results of ongoing clinical trials are needed to confirm these data.29,30 As for the maintenance immunosuppression, it is likely that the strategy has to be adapted individually, based on the level of immunologic risk (mainly determined by the presensitization status). Minimization of calcineurin inhibitors (CNIs) is associated with an increased risk of DSA generation31 and, in the absence of specific clinical indications, should be restricted to situations with a particularly low immunologic risk. Belatacept is a promising alternative to CNI. In the long-term analysis of the BENEFIT and BENEFIT-EXT trials, patients treated with Belatacept had lower rates of DSAs than patients treated with Ciclosporin.32 This beneficial effect could be partly explained by the fact that, in contrast with CNI, Belatacept is administered intravenously monthly, which limits noncompliance, a main risk factor for de novo DSA generation.5,6 It is also important to mention that the control group was treated with Ciclosporin, which is associated with a higher risk of rejection than tacrolimus33 and that patients treated with Belatacept had higher rates of cellular rejection.34

The management of recipients with DSAs remains a challenge. Because of their deleterious impact on allograft outcomes, preformed DSAs were for a long time considered a contraindication to transplantation. Over the last decade, several teams have reported that transplantation can in fact sometimes be performed across the anti-HLA antibody barrier, in particular when preformed DSAs are not associated with a positive CDC crossmatch.35 These patients usually receive a combination of plasmapheresis and intravenous immunoglobulins (IV Igs) with or without anti-CD20 monoclonal antibodies.36 Long-term results with these protocols have been mitigated. In a recent cohort of 95 kidney-transplant patients with high levels of pretransplant DSA, AMR occurred during the first year in 32.6% of patients, and the rate of chronic AMR was high, close to 40% at 1 y.37 This incites transplant physicians to envisage transplantations across the anti-HLA antibody barrier with extreme caution and encourages further studies to determine the conditions in which such procedures are beneficial for patients.

The appearance of DSA after transplantation (ie, de novo DSA) is also a major concern since it is associated with AMR and allograft loss.3,15,38 The management of AMR is particularly challenging.39 This is explained by the phenotypic and prognostic heterogeneity of AMR and, importantly, by the lack of effective treatment. Of note, the lack of effective treatment for AMR is probably also 1 reason why cellular rejection, which can be treated by steroids or thymoglobulin initially got more attention than AMR. Currently, standard of care for AMR principally relies on (1) DSA removal by plasmapheresis or immunoabsorption and (2) blockade of antibody-mediated effector functions by IVIg.40 This approach has been shown to slow the destructive process of AMR but fails to completely stop it.38,40,41 Overall, anti-CD20 monoclonal antibodies and proteasome inhibitors, which target B cells and plasma cells respectively showed only limited (if any) effect on AMR outcomes, which contrasts with significant side effects and costs.42-45 Recent treatments such as complement inhibitors (C5 or C1 inhibitors),46,47 IL-6 receptor blockers (tocilizumab),48 or IgG-degrading enzymes (IdeS)49 have shown encouraging results in specific situations, but it is likely that these approaches, which are restrained to terminal effector mechanisms (but do not impact DSA production), will be ineffective in entirely stopping the AMR destructive process.

HUMORAL ALLOIMMUNITY IN VCA RECIPIENTS: CAN WE EXTRAPOLATE FROM “CONVENTIONAL” TRANSPLANT RECIPIENTS?

The susceptibility of vascularized organ transplants to the humoral alloimmune response considerably varies according to the type of transplanted organ. Liver is considered as being relatively protected50 while kidney, heart, lung, or pancreas are known to be sensitive.1-6 The case of VCA is complex because several tissues with different immunologic characteristics and different regeneration capabilities are transplanted as a single functional unit. This makes it difficult to determine the clinical significance of humoral alloreactivity.

Clinical Significance of Humoral Alloreactivity in VCA Recipients

Two factors have to be considered: the risk of developing DSA after VCA transplantation and the pathogenicity of these DSAs for the VCA graft.

Incidence of De Novo DSAs After VCA

The incidence of de novo DSA after VCA is difficult to estimate given the small size of patient cohorts. When analyzing the Lyon University Hospital cohort of 10 VCA recipients (7 hand recipients and 3 face recipients) followed during 10.5 y in median [range: 3–19 y], we found that 2 of them transiently developed low titer (ie, MFI <1000) DSA and 2 stably developed DSA at a significant MFI level (Petruzzo et al51 and personal unpublished data). These patients had all received induction by thymoglobulin and a standard maintenance tritherapy including tacrolimus (the tacrolimus trough level targets were 8–12 µg/L during the first year and 5–7 µg/L onwards). There was no significant difference between the tacrolimus levels of recipients with or without DSA. The Louisville group reported that only 1 out of 10 (10%) hand transplant recipients developed de novo DSA after VCA.52 This occurred 6 y posttransplant after reduction of tacrolimus as a result of changes in kidney function, which suggests that minimization of CNIs is associated with an increased risk of dnDSA even several years after VCA transplantation. The Oxford group recently compared the incidence of de novo DSA in 18 patients who received combined intestinal and abdominal wall VCA and 14 who received an intestinal or multivisceral transplant only.53 Fewer recipients developed de novo DSA in the VCA group (37.5% versus 61.5% in the VCA and non-VCA group, respectively). The authors concluded that VCA does not increase the risk of de novo DSA.

In sum, the incidence of dnDSA in VCA recipients seems relatively low when compared with what reported in SOT recipients. A first explanation could be that VCA recipients are more closely monitored than SOT recipients and thereby probably more compliant (noncompliance being a main risk factor for de novo DSA generation5,6). One may also hypothesize that circulating DSAs are less frequently detected because they are bound to the allograft. This is in line with the repeated observation of a flair in de novo DSA incidence immediately after the surgical removal of a VCA (Kaufman et al54 and personal unpublished data). Highly vascularized tissues such as bone, skin, and muscle could be responsible for a significant adsorption of DSAs. Finally, the relatively low frequency of dnDSA in VCA recipients could also be explained by the immunologic peculiarities of VCA. It is possible that the quantitative and qualitative specificities of the allogenic stimulation in the settings of VCA shape the nature and the magnitude of the B cell response. For instance, the massive release of danger signals associated with ischemia-reperfusion injuries of multiple tissues could induce the expansion of regulatory B cells, as this is the case in vitro when B cells are stimulated with high doses of TLR ligands.55,56 The presence of donor cells with regulatory properties in VCA-specific tissues such as bone marrow could also influence B cell responses.

Pathogenicity of DSAs

As stated previously, DSAs can only be pathogenic if they can bind to the accessible allogenic targets expressed by graft vasculature.15 This is the case in VCA transplantation, in which donor vessels are anastomosed with those of the recipients.

Few clinical reports indicate that DSA could be pathogenic for VCA grafts.

Chandraker et al57 reported the case of a face transplantation performed in the presence of preformed DSAs. The immunosuppressive protocol included thymoglobulin, postoperative plasmapheresis, and standard maintenance immunosuppression, including tacrolimus. Erythema and swelling of the graft were observed 5 d after transplantation. Because these symptoms were concomitant with a rise in DSA levels and the presence of C4d deposits on histologic examination of skin biopsies, the authors retained the diagnosis of AMR. This rejection episode was treated with a combination of plasmapheresis, eculizumab, bortezomib, and alemtuzumab. Although the initial outcome was favorable, the last update presented at the ISVCA congress in October 2019 indicated that the patient subsequently developed progressive necrosis of the graft.

As for de novo DSAs, Weissenbacher et al58 reported the case of a forearm-transplanted patient that developed de novo DSA 9 y after transplantation and histologic lesions suggestive of AMR. This episode occurred after 6 cellular rejections. The recipient received 1 dose of rituximab, which induced both a clinical and serologic response. The blood vessels however continued to be positive for C4d.

In Lyon University Hospital cohort (n = 10 VCA recipients), 4 patients have developed de novo DSAs after transplantation. The 2 (1 face and 1 bilateral hand transplantation) with transient and low DSA titers did not experience any particular problem, in contrast with the remaining 2 that had a history of poor IS drug compliance and had developed higher and more stable DSA titers. The first case (reported in Morelon et al59) is a face transplant recipient, who developed de novo class II DSA (peak MFI = 12 500), 7.5 y after transplantation. Some months later, the sentinel skin graft underwent necrosis, and microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. The patient did not respond to steroid pulses, IV Igs, plasmapheresis, bortezomib, and eculizumab, and partially lost her graft. The second case is a bilateral hand transplant recipient that also developed de novo class II DSAs 6.5 y after transplantation (but at lower titer: MFI peak <3000). Five years after the first DSA detection, the patient developed finger necrosis requiring partial amputation. Explanted fingers presented clear allograft vasculopathy lesions compatible with the diagnosis of chronic AMR and DSAs could be eluted from the tissue. Progression of chronic vascular rejection led to graft explantation 1 y later, and DSA became detectable at high MFI level shortly after. It is tempting to conclude from these 2 cases that, depending on titer, DSAs are responsible for acute and chronic AMR in VCA (as in “conventional” organ transplantations). However, it shall be mentioned that both patients had also presented several episodes of cellular skin rejection with perivascular infiltration, which may also have caused the chronic vascular lesions. In line with this idea, a previous study has reported that de novo DSA detection in upper extremity recipients is most often associated with T cell–mediated rejection,60 which confirms that humoral and cellular rejections are a 2-nested process.

Given the small numbers of patients and the heterogeneity of the clinical observations, experimental studies are necessary to better determine the pathogenicity of DSA in VCA recipients. One can imagine a passive transfer of DSA to murine hindlimb immunodeficient recipients, as previously done in heart or islet transplantation models.13,29

Finally, given the differences in terms of susceptibility to immune aggression or regeneration capacities of tissues such as nerve, muscle, or skin, DSAs probably have a heterogeneous impact on different allograft functions. This makes the diagnosis of AMR (ie, the objectivation and evaluation of the global loss of allograft function) more difficult.

Diagnosis of AMR in VCA Recipients

Although tempting, the possibility to extrapolate the AMR diagnostic criteria established in SOT to VCA patients is uncertain. As done in SOT, the diagnostic values of C4d staining, microvascular lesions on skin biopsies, or detection of circulating DSA have to be questioned in VCA recipients. The presence of C4d staining in upper-extremity recipients has been described.61 However, the diagnostic value of C4d in VCA remains unclear. To investigate whether C4d deposition would be useful in monitoring rejection in human composite tissue allografts, our team has examined 60 mucocutaneous formalin-fixed, paraffin-embedded, and 4 frozen biopsy specimens from 4 patients with composite tissue allografts (3 hands and 1 face) taken during a period of 7 d to 7 y after transplantation.62 Skin biopsies from nontransplant patients with inflammatory dermatoses were positive and served as a positive control. C4d deposition was not found in any of the specimens studied, including in the ones with pathologic signs of TCMR (no DSAs were detected in any of the patients of this study). Among the 4 patients who transiently or stably developed DSA in our cohort, 1 had a positive C4d staining51 (Figure 2A). C4d staining has however also been described during rejection of a hand transplant in the absence of DSA and was also positive on skin biopsies in the absence of clinical signs of rejection.61

FIGURE 2.
FIGURE 2.:
Histologic lesions suggestive of antibody-mediated rejection in VCA recipients. A, C4d deposition in dermal capillaries in a hand-allograft recipient (hematoxylin-eosin, original magnification ×250). B, Banff grade III skin rejection characterized by a dense lymphocytic dermal infiltration penetrating the epidermis, interface dermatitis, apoptotic keratinocytes in the epidermis, and capillary thrombosis (seen on the left) (hematoxylin-eosin, original magnification ×250). C, Graft vasculopathy in a postamputation specimen of a hand-allograft recipient characterized by myo-intimal thickening of the medial arterial layer, luminal narrowing and a thrombosis, and a dense periarteriar lymphocytic infiltrate (hematoxylin-eosin, original magnification ×40). VCA, vascularized composite allotransplantation.

Other histologic lesions suggestive of an AMR process have been described in VCA recipients. Weissenbacher et al58 reported the presence of B cell–containing lymphoid aggregates in the skin allograft of a patient who developed de novo DSA. These tertiary lymphoid structures have been reported to be present in almost every chronically rejected grafts and could be the site of a local “intragraft” DSA generation.23,24,63 Our team observed graft vasculopathy in a postamputation specimen of a hand-allograft recipient (Figure 2B) and capillary thrombosis in the upper dermis in 2 of 10 VCA recipients64 (Figure 2C). One of them had developed DSAs some months before and had occasional C4d deposits in cutaneous capillaries. Whether this feature is characteristic of AMR in VCA is uncertain. We also observed that 2 out of 4 hand recipients with persisting DSA developed graft arteriosclerosis based on an analysis of the radial and ulnar arteries by high-resolution ultrasound biomicroscopy. Another team observed the same lesions in 5 out of 6 hand recipients, 3 of them without detectable DSA.54 This could represent a way to detect allograft vasculopathy and signal a possible ongoing AMR process, but this approach likely lacks specificity.

As is the case with “conventional” SOT recipients, histologic features consistent with AMR in the absence of detectable circulating DSA do not exclude humoral alloreactivity in VCA recipients. In a hand allograft recipient with severe rejection lesions, DSAs appeared 2 d after amputation, suggesting that DSAs were not detected in the circulation because they were trapped in the allograft.54 Our group made a similar observation and could validate the hypothesis by showing that DSA could be eluted from the explanted graft (personal unpublished data). As in “conventional” SOT, vascular lesions can also be caused by non-HLA antibodies that are not detected by routine assays.25

In sum, none of the classic features of AMR, that is, C4d deposition, histologic lesions, and DSA detection, are specific enough to ensure a reliable diagnosis of AMR in VCA patients. AMR is often envisaged by clinicians based on an incomplete body of clinical, histologic, serologic, and radiologic arguments. There is a strong need to identify specific criteria for AMR in VCA recipients. Given the low number of cases, the solution could also be found in animal models.

Management of Donor-specific Humoral Alloreactivity in VCA Recipients

In SOT, desensitization protocols in patients with preformed DSA have been associated with mitigated results. The only patient who received VCA with a positive T cell and B cell crossmatch received induction by thymoglobulin, plasmapheresis, and a conventional immunosuppressive regimen.57 This treatment failed to prevent AMR (that occurred on postoperative day 5), which argues for more intensive desensitization protocols in VCA patients. Wang et al65 proposed to add syngeneic hematopoietic stem cell transplantation (HSCT) to conventional immunosuppression based on data obtained in presensitized rats receiving a hindlimb transplant. HSCT is associated with significant treatment-related mortality both in patients with hematologic malignancies and autoimmune diseases. Is this risk acceptable in patients receiving a limb transplantation which is not a life-saving procedure? Or should this approach be considered only in face transplant recipients who are suffering from a life-threatening condition? VCA recipients are probably healthier than the preponderance of HSCT recipients and could experience a lower complication rate after HSCT.

Data on the treatment of AMR in VCA patients are also extremely scarce. The presensitized patient who developed AMR on day 5 was treated by a combination therapy consisting of plasmapheresis, eculizumab, bortezomib, and alemtuzumab, which allowed for decreased DSA levels and satisfactory short-term clinical evolution.57 However, this patient developed progressive necrosis and accelerated graft loss evocative of chronic AMR. A hand recipient who developed de novo DSA and AMR 9 y after transplantation was treated by steroids, an increase in maintenance immunosuppression, and rituximab. This treatment was also associated with favorable short-term outcomes. Finally, our face transplant recipient that developed high level of DSA and acute AMR did not respond to any of the approaches tested (including steroid pulses, IV Igs, plasmapheresis, bortezomib, and eculizumab).59 However, given this extremely small clinical experience and the lack of clinical hindsight, desensitization protocols and treatment of AMR in VCA recipients should be based on those currently recommended in “conventional” SOT recipients.

CONCLUSION

Like the recipients of a “conventional” SOT, VCA recipients can develop DSA, the generation of which is favored by insufficient immunosuppression. However, in the absence of clearly defined histologic features, the diagnosis of AMR in VCA remains difficult. Experience from “conventional” transplantations has shown that DSAs, which are sequestrated in the circulation because of their size, bind to allogeneic endothelial cells and trigger inflammation of the graft vasculature. This pathophysiology could also apply for VCA, as suggested by the recent reports of late ischemic VCA losses in patients with DSA. Indeed, in both cases chronically rejected VCA had typical features of graft vasculopathy. However, lessons learned in solid organ transplantation may not systematically apply to VCA. Given the low number of VCA cases, the use of animal models might facilitate the identification of specific histologic criteria for AMR and a better characterization of DSA pathogenicity in VCA recipients.

Finally, it shall be kept in mind that, in the absence of an efficient treatment against AMR, the prevention of DSA generation remains the best prospect to improve the outcomes of (“conventional” transplantations and) VCAs.

ACKNOWLEDGMENTS

The authors wish to thank the surgical team, which played an instrumental role in the success of Lyon University Hospital’s VCA program, in particular Prof Lionel Badet and Prof Palmina Petruzzo (from the Urology Department of Edouard Herriot Hospital, Lyon France), Dr Aram Gazarian (Clinique du Parc, Lyon, France), and Prof Bernard Devauchelle (from the Maxillofacial Surgery Department of Amiens University Hospital).

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