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Chapter 114 : Evaluation of the Humoral Response in Transplantation

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Evaluation of the Humoral Response in Transplantation, Page 1 of 2

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Abstract:

Antibodies of the IgG class can damage tissues in a variety of ways, including (i) directly through complement activation, (ii) indirectly through the deposition of immune complexes, and (iii) indirectly through the recruitment of cytotoxic or inflammation-inducing cells. Very high levels of antibody result in hyperacute rejection and graft failure, an outcome that can easily be avoided by the performance of a lymphocyte crossmatch test prior to transplantation. In contrast, clear elucidation of the relevance of donor-reactive antibodies of various strengths and specificities and of antibodies that arise after transplantation has been hampered by inadequate technologies and lack of reimbursement for posttransplant monitoring of antibodies. Nonetheless, a deleterious effect of antibody specific for mismatched donor HLA antigens has been demonstrated for nearly every type of organ and tissue that has been transplanted in sufficient numbers, including hematopoietic stem cells and, possibly, composite tissues. There is overwhelming evidence indicating that anti-HLA antibodies are involved in hyperacute, acute, and chronic rejection of organs (1). In mismatched bone marrow transplants, there is a risk of immunocompetent tissues from sensitized patients producing antibody to recipient tissues as well as a risk of recipients making antidonor antibodies. In theory, antibodies specific for any antigen on transplanted tissue should be capable of damaging the transplant. The best-known antibodies that are injurious to allografts are those specific for antigens of the HLA and ABO systems. Potential deleterious effects of other antibodies are being recognized increasingly. A discussion of those is beyond the scope of this chapter, and the interested reader is directed to two excellent reviews on this topic (2, 3). The focus of this chapter will be HLA-specific antibodies, and we will use the term donor-specific antibody (DSA) to refer to antibody(ies) specific for donor HLA antigens.

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114
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Figures

Image of FIGURE 1
FIGURE 1

Results of serum tested on a phenotype panel. The specificity of the antibody can readily be discerned by the clustering of DR52 phenotypes. Note that the three phenotypes bearing DR8, an antigen that strongly cross-reacts with DR52, are interspersed among the DR52-bearing phenotypes. Val., value.

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114
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References

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1. Leffell MS, Zachary AA. 2010. Anti-allograft antibodies: some are harmful, some can be overcome, and some may be beneficial. Discov Med 9:478484.[PubMed]
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4. Willicombe M, Brookes P, Sergeant R, Santos-Nunez E, Steggar C, Galliford J, McLean A, Cook TH, Cairns T, Roufosse C, Taube D. 2012. De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy. Transplantation 94:172177.[CrossRef].[PubMed]
5. Gilbert M, Paul S, Perrat G, Giannoli C, Pouteil Noble C, Morelon E, Rigal D, Dubois V. 2011. Impact of pretransplant human leukocyte antigen-C and -DP antibodies on kidney graft outcome. Transplant Proc 43:34123414.[CrossRef].[PubMed]
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7. Bachelet T, Couzi L, Guidicelli G, Moreau K, Morel D, Merville P, Taupin JL. 2011. Anti-Cw donor-specific alloantibodies can lead to positive flow cytometry crossmatch and irreversible acute antibody-mediated rejection. Am J Transplant 11:15431544.[CrossRef].[PubMed]
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9. Philogene MC, Zachary AA. 2013. Assessing immunologic risk factors in transplantation. Expert Rev Clin Immunol 9:773779.[CrossRef].[PubMed]
10. Vlaar AP, Juffermans NP. 2013. Transfusion-related acute lung injury: a clinical review. Lancet 382:984994.[CrossRef].[PubMed]
11. Zachary AA, Leffell MS. 2008. Detecting and monitoring human leukocyte antigen-specific antibodies. Hum Immunol 69:591604.[CrossRef].[PubMed]
12. Zachary AA, Klingman L, Thorne N, Smerglia AR, Teresi GA. 1995. Variations of the lymphocytotoxicity test. An evaluation of sensitivity and specificity. Transplantation 60:498503.[PubMed].[CrossRef]
13. Earley MC, Vogt RF Jr, Shapiro HM, Mandy FF, Kellar KL, Bellisario R, Pass KA, Marti GE, Stewart CC, Hannon WH. 2002. Report from a workshop on multianalyte microsphere assays. Cytometry 50:239242.[CrossRef].[PubMed]
14. Zachary AA, Lucas DP, Detrick B, Leffell MS. 2009. Naturally occurring interference in Luminex assays for HLA-specific antibodies: characteristics and resolution. Hum Immunol 70:496501.[CrossRef].[PubMed]
15. Badders JL, Houp JA, Sholander JT, Leffell MS, Zachary AA. 2010. Considerations in interpreting solid phase antibody data. Hum Immunol 71:18.[CrossRef]
16. El-Awar N, Nguyen A, Almeshari K, Alawami M, Alzayer F, Alharbi M, Sasaki N, Terasaki PI. 2013. HLA class II DQA and DQB epitopes: recognition of the likely binding sites of HLA-DQ alloantibodies eluted from recombinant HLA-DQ single antigen cell lines. Hum Immunol 74:11411152.[CrossRef].[PubMed]
17. Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G. 2013. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 95:1947.[CrossRef].[PubMed]
18. Hahn AB, Land GA, Strothman RM. 2000. ASHI Laboratory Manual, 4th ed. ASHI, Lenexa, KS.
19. Emery P, Mach B, Reith W. 1993. The different level of expression of HLA-DRB1 and -DRB3 genes is controlled by conserved isotypic differences in promoter sequence. Hum Immunol 38:137147.[PubMed].[CrossRef]
20. Schwartz A, Fernández Repollet E, Vogt R, Gratama JW. 1996. Standardizing flow cytometry: construction of a standardized fluorescence calibration plot using matching spectral calibrators. Cytometry 26:2231.[CrossRef].[PubMed]
21. Zachary AA, Braun WE. 1985. Calculation of a predictive value for transplantation. Transplantation 39:316318.[PubMed].[CrossRef]
22. Zachary AA, Sholander JT, Houp JA, Leffell MS. 2009. Using real data for a virtual crossmatch. Hum Immunol 70:574579.[CrossRef].[PubMed]
23. Hetrick SJ, Schillinger KP, Zachary AA, Jackson AM. 2011. Impact of pronase on flow cytometric crossmatch outcome. Hum Immunol 72:330336.[CrossRef].[PubMed]
24. Schnaidt M, Weinstock C, Jurisic M, Schmid-Horch B, Ender A, Wernet D. 2011. HLA antibody specification using single-antigen beads—a technical solution for the prozone effect. Transplantation 92:510515.[CrossRef].[PubMed]
25. Smith JD, Hamour IM, Banner NR, Rose ML. 2007. C4d fixing, Luminex binding antibodies—a new tool for prediction of graft failure after heart transplantation. Am J Transplant 7:28092815.[CrossRef].[PubMed]
26. Fontaine MJ, Kuo J, Chen G, Galel SA, Miller E, Sequeira F, Viele M, Goodnough LT, Tyan DB. 2011. Complement (C1q) fixing solid-phase screening for HLA antibodies increases the availability of compatible platelet components for refractory patients. Transfusion 51:26112618.[CrossRef].[PubMed]
27. Sutherland SM, Chen G, Sequeira FA, Lou CD, Alexander SR, Tyan DB. 2012. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant 16:1217.[CrossRef].[PubMed]
28. Zeevi A, Lunz J, Feingold B, Shullo M, Bermudez C, Teuteberg J, Webber S. 2013. Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant 32:98105.[CrossRef].[PubMed]
29. Locke JE, Zachary AA, Warren DS, Segev DL, Houp JA, Montgomery RA, Leffell MS. 2009. Proinflammatory events are associated with significant increases in breadth and strength of HLA-specific antibody. Am J Transplant 9:21362139.[CrossRef].[PubMed]
30. Montgomery RA, Zachary AA, Racusen LC, Leffell MS, King KE, Burdick J, Maley WR, Ratner LE. 2000. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 70:887895.[PubMed].[CrossRef]
31. Sonnenday CJ, Ratner LE, Zachary AA, Burdick JF, Samaniego MD, Kraus E, Warren DS, Montgomery RA. 2002. Preemptive therapy with plasmapheresis/intravenous immunoglobulin allows successful live donor renal transplantation in patients with a positive cross-match. Transplant Proc 34:16141616.[PubMed].[CrossRef]
32. Tyan DB, Li VA, Czer L, Trento A, Jordan SC. 1994. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 57:553562.[PubMed].[CrossRef]

Tables

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TABLE 1

Patient information

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114
Generic image for table
TABLE 2

Assay characteristics

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114
Generic image for table
TABLE 3

Advantages and disadvantages of different assays

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114
Generic image for table
TABLE 4

Quality control

Citation: Sikorski P, Vega R, Lucas D, Zachary A. 2016. Evaluation of the Humoral Response in Transplantation, p 1091-1102. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch114

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