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Review
. 2023 Jul-Aug;30(4):e12816.
doi: 10.1111/xen.12816. Epub 2023 Aug 7.

Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Zahra Habibabady  1 , Gannon McGrath  1 , Kohei Kinoshita  1 , Akihiro Maenaka  1 , Ileka Ikechukwu  1 , Gabriela F Elias  1 , Tjasa Zaletel  1 , Ivy Rosales  2 , Hidetaka Hara  3 , Richard N Pierson 3rd  1 , David K C Cooper  1
Affiliations
Review

Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Zahra Habibabady et al. Xenotransplantation. 2023 Jul-Aug.

Abstract

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.

Keywords: B cells; anti-pigm; antibodies; antibody-mediated; complement; genetically-engineered; pig; plasma cells; rejection.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

D.K.C.C. is a consultant to eGenesis Bio of Cambridge, MA, but the opinions expressed in this article are those of the authors, and do not necessarily reflect those of eGenesis. No other author reports a conflict of interest.

Figures

FIGURE 1
FIGURE 1
Development of natural IgM (top) and IgG (bottom) antibodies to red blood cells (RBCs) from pigs of various phenotypes in infant and adult baboons. Geometric mean (GM) binding and age correlation of baboon serum IgM (top) and IgG (bottom) antibodies to wild-type (WT, left), α1,3-galactosyltransferase gene-knockout (GTKO, middle), and triple-knockout (TKO, right) RBCs. There was an increase in IgM during the first year of life. Although adult baboons had higher levels of IgG binding to WT and TKO pig RBCs, there was no increase in IgG binding to GTKO pig RBCs. Note the different scales on the y axis between IgM and IgG. (Modified from Hara H, et al. Xenotransplantation. 2021 Apr 30:e12692. https://doi.org/10.1111/xen.12692).
FIGURE 2
FIGURE 2
Human serum antibody binding to WT and TKO pig red blood cells. (Top) Geometric mean (GM) binding and age correlation of human serum IgM (A) and IgG (B) antibodies to wild-type (WT) pig red blood cells (RBCs). There is a steady increase in IgM and IgG during the first year of life. (Bottom): Geometric mean (GM) binding and age correlation of human serum IgM (A) and IgG (B) antibodies to TKO pig RBCs. There is virtually no increase in IgM or IgG antibodies during the first year of life, and a very low level of antibodies in adults. The dotted lines indicate no IgM or IgG binding. (Note the great difference in the scale on the y axis between Top vs. Bottom). (Reproduced with permission from Li Q 2020).
FIGURE 3
FIGURE 3
Schema of complement system (with indications where anti-complement agents or human complement-regulatory proteins play a role). Classical pathway (left): Activated by binding of antibodies to antigens, which triggers C1q, activates C1r, C1s, then cleaves C4 and C2 to form C4b2a (C3 convertase). Lectin pathway (middle): One of MBL, ficolin (Fcn) −1, −2, and −3, and collectin 10/11 and collectin-P (CL), recognizes lipopolysaccharides, and so forth, and binds to one of the MASP-1, MASP-2, and MASP-3, forming C4b2a (C3 convertase). C4b2a from the classical or lectin pathway cleaves C3 into C3a and C3b. C3b binds to C4b2a to form C4b2a3b (a C5 convertase). Alternative pathway (right): C3 undergoes spontaneous hydrolysis to form C3(H2O), which binds to factor B, forming an unstable C3(H2O)Bb, generating more C3b. Activation of C3 in the presence of factor B and factor D results in the formation of C3bBb (C3 convertase). Properdin stabilizes C3 and C5 convertase, and enhances the amplification loop of C3 activation, then generating C3bBb3b (a C5 convertase). Activation of MAC (bottom): The C5 convertase cleaves C5 into C5a and C5b, the latter interacting with C6–C9 to form the MAC (C5b-9), which in turn results in lysis, damage, or activation of target cells. The complement system is tightly regulated by soluble inhibitors, including C1-INH, factor H, factor I, C4BP, anaphylatoxin inhibitor inactivating the anaphylatoxins (e.g., C5a to C5adesArg), vitronectin, S-protein, and clusterin maintaining continuous low-grade activation in the fluid phase in check. Host cell membranes are equipped with a number of inhibitors to protect them against attack by complement, including CD46, CD55, thus controlling C4 and C3 activation. CD59 protects against final assembly of the membrane attack complex C5b-9. Eculizumab and tesidolumab inhibit cleavage of C5 to C5a and C5b and the formation of the C5b-9. (MBL = Mannose-binding lectin; MASP = Mannose-binding lectin-associated serine proteases; C1-INH = C1 esterase inhibitor; C4BP [I do not see this in the figure] = C4-binding protein; CD55 = DAF, decay accelerating factor; CD46 = MCP, membrane cofactor protein); CD59 = MAC-IP, membrane attack complex C5b-9 inhibitory protein).
FIGURE 4
FIGURE 4
Serum C-reactive protein (C-RP) responses to gene-edited pig kidney or artery patch transplants in immunosuppressed baboons being treated with or without tocilizumab (anti-IL-6R mAb). (Reproduced with permission from Li T, et al. Transplantation. 2017;101:2330–2339).
FIGURE 5
FIGURE 5
Histopathology of AMR in a pig kidney. (Top) Glomerular thrombotic microangiopathy in acute AMR. (A) Mononuclear and polymorphonuclear cells fill glomerular capillary lumina, associated with fragmentation of red blood cells. Part of the glomerulus shows severe distortion of the glomerular architecture (arrow), associated with mesangiolysis and loss of capillaries and endothelial cells. (B) Thrombotic microangiopathy in a glomerulus showing shrinkage of the glomerular tuft and a fibrin thrombus (arrow) in the glomerular hilar arteriole. Apoptotic cells are seen in the lumen of a distal tubule. Marked interstitial edema is also present. (Bottom) Severe glomerular thrombotic microangiopathy in acute AMR. (A) Glomerulus with complete loss of endothelial and capillary lumina replaced by microthrombi. The glomerular hilar arteriole also shows thrombi with red cell fragmentation. (B) Peritubular capillary thrombotic microangiopathy (arrows) in a background of interstitial edema and hemorrhage.
FIGURE 6
FIGURE 6
Histopathology of AMR in a pig heart. (A) Diffuse edema and congestion, focal areas of hemorrhage in early acute AMR (H&E, 100×). Foci of interstitial mononuclear infiltrates are also present. (B) Interstitial hemorrhage with individual myocyte necrosis (arrows) (H&E, 400×). (C) Arterial thrombus (arrow) in severe acute AMR, associated with diffuse edema and beginning infarction and necrosis of adjacent myocardium. (D) Immunohistochemistry by peroxidase using C4d showing deposition in arterial endothelium and capillaries.
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