LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Daga, Sunil
Languages: English
Types: Doctoral thesis
Subjects: RC0254
Abstract\ud \ud Following five decades of kidney transplantation, increasingly high risk immunological kidney transplantation (which previously was considered as sub-optimal) are carried out. The risk stratification with the current available assays have allowed safe transplantation in low risk non-sensitised patients and direct transplantation in high risk highly sensitised patients by removal of circulating donor specific antibodies (DSA) with reasonable outcomes. However, a large number of patients with chronic kidney disease and with low or intermediate antibody levels measured by current assay, the best way forward is uncertain resulting in denial of transplantation in some cases. Whilst in other cases, the solid phase Luminex assay may under or overestimate the risks of rejection and graft failure following direct kidney transplantation.\ud \ud Currently only IgG-class of DSA is considered immunologically important and routinely measured in clinical laboratories. Other bio-physiological characteristics such as class, sub-class and binding kinetics of DSA may be more specific for risk stratification of immunological risks. In this thesis, we studied effect of de novo IgM class of HLA-specific antibodies on outcome of kidney transplantation and characterised binding kinetics and strength of HLA-specific antibodies.\ud \ud De novo IgM or IgG HLA-specific responses alone were not associated with adverse outcomes following kidney transplantation. Presence of both IgM and IgG responses, however, was associated with poor graft function at 36 months. There was no temporal relationship of antibody response and episodes of rejections. De novo Donor specific responses were less frequent compared to non-specific responses. A shorter follow-up and use of modern triple immunosuppressant therapy (Tacrolimus, Mycophenolate and Steroid) may explain this.\ud \ud Binding kinetics measured by biosensor assay- surface plasmon resonance (SPR) on purified monoclonal HLA-specific antibodies showed binding kinetics and strength differed between HLA alleles despite same epitope and paratope interactions. There was a tendency towards higher affinity and faster association rate for HLA protein that was the initial immunizing antigen for the corresponding monoclonal HLA-specific antibodies. The dissociation constant (KD) of human monoclonal HLA-specific antibodies range between 10-8 to 10-10 M. Thermodynamic analysis showed higher Gibbs free energy released for interactions with higher binding strength. The binding strength of mixed monoclonal HLA-specific antibodies is generally average of the strength of individual monoclonal HLA-specific antibodies.\ud \ud Enriched polyclonal HLA-specific antibodies from clinical sample gave distinct binding response on bio-sensor based on SPR assay. Quantification of polyclonal HLA-specific antibodies using sandwich ELISA and SPR allowed quantitative measurement of binding kinetics and strengths. A range of binding strength was observed between patients and within same patient antibodies of different affinities was observed. Thus the antibodies could be grouped in four groups based on the strength of binding and this can serve as additional biomarker for risk stratifications.\ud
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • affinity .................................................................................................................................................256
    • Purification of polyclonal HLA-specific antibodies..............................................................260
    • Quantification of HLA-specific antibodies ..........................................................................292
    • (rejection and graft loss).................................................................................................................321
    • Appendix A - Kidney Advisory Group KAG(13)34................................................................363
    • Appendix B - KIDNEY ADVISORY GROUP - KAG(14)45a ......................................................364
    • Appendix C - Publications / Abstracts.................................................................................368
    • 3.5. Alloantibodies to DR11 fix complement [1] Gentry SE, Segev DL, Montgomery RA. A comparison of populations served by
    • 2005;5:1914-21. [2] Segev DL, Gentry SE, Melancon JK, Montgomery RA. Characterization of waiting
    • 2005;5:2448-55. [3] Claas FH. Clinical relevance of circulating donor-specific HLA antibodies. Curr
    • Opin Organ Transplant 2010;15:462-6. [4] Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and
    • pathogenesis. J Am Soc Nephrol 2007;18:1046-56. [5] Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, Hidalgo LG, et al. Antibody-
    • failure. Am J Transplant 2009;9:2520-31. [6] Gaston RS, Cecka JM, Kasiske BL, Fieberg AM, Leduc R, Cosio FC, et al. Evidence
    • failure. Transplantation 2010;90:68-74. [7] Jindra PT, Jin YP, Rozengurt E, Reed EF. HLA class I antibody-mediated
    • endothelial cell proliferation via the mTOR pathway. J Immunol 2008;
    • 180:2357-66. [8] Narayanan K, Jendrisak MD, Phelan DL, Mohanakumar T. HLA class I antibody
    • mediated accommodation of endothelial cells via the activation of PI3K/cAMP
    • dependent PKA pathway. Transpl Immunol 2006;15:187-97. [9] Rahimi S, Qian Z, Layton J, Fox-Talbot K, Baldwin 3rd WM, Wasowska BA. Non-
    • rejection of cardiac allografts. Am J Transplant 2004;4:326-34. [10] Wasowska BA. Mechanisms involved in antibody- and complement-mediated
    • allograft rejection. Immunol Res 2010;47:25-44. [11] Amico P, Honger G, Mayr M, Steiger J, Hopfer H, Schaub S. Clinical relevance of
    • beads. Transplantation 2009;87:1681-8. [12] Gupta A, Sinnott P. Clinical relevance of pretransplant human leukocyte
    • risk factor. Hum Immunol 2009;70:618-22. [13] van den Berg-Loonen EM, Billen EV, Voorter CE, van Heurn LW, Claas FH, van
    • Transplantation 2008;85:1086-90. [14] Busch R, Pashine A, Garcia KC, Mellins ED. Stabilization of soluble, low-affinity
    • HLA-DM/HLA-DR1 complexes by leucine zippers. J Immunol Methods
    • 2002;263:111-21. [15] El-Awar N, Terasaki PI, Cai J, Deng CT, Ozawa M, Nguyen A. Epitopes of the
    • HLA-A, B, C, DR, DQ and MICA antigens. Clin Transpl 2007;0:175-94. [16] Bodmer J, Bodmer W, Heyes J, So A, Tonks S, Trowsdale J, et al. Identification of
    • USA 1987;84:4596-600. [17] Cano P, Fernandez-Vina M. Two sequence dimorphisms of DPB1 define the
    • immunodominant serologic epitopes of HLA-DP. Hum Immunol 2009;
    • 70:836-43. [18] Klohe E, Pistillo MP, Ferrara GB, Goeken NE, Greazel NS, Karr RW. Critical role
    • of HLA-DR beta 1 residue 58 in multiple polymorphic epitopes recognized by
    • xenogeneic and allogeneic antibodies. Hum Immunol 1992;35:18-28. [19] Zachary AA, Lucas DP, Detrick B, Leffell MS. Naturally occurring interference in
    • Hum Immunol 2009;70:496-501. [20] Reed EF, Rao P, Zhang Z, Gebel H, Bray RA, Guleria I, et al. Comprehensive
    • detection of antibodies to HLA. Am J Transplant 2013;13:1859-70. [21] Duquesnoy RJ, Awadalla Y, Lomago J, Jelinek L, Howe J, Zern D, et al.
    • 2008;18:352-60. [22] Duquesnoy RJ, Marrari M, Jelenik L, Zeevi A, Claas FH, Mulder A. Structural
    • Ig-binding, C1q-binding and lymphocytotoxicity assays. Hum Immunol
    • 2013;74:1271-9. [23] Bosch A, Llorente S, Diaz JA, Salgado G, Lopez M, Boix F, et al. Low median
    • Hum Immunol 2012;73:522-5. [24] Muro M, Gonzalez-Soriano MJ, Salgado G, Lopez R, Boix F, Lopez M, et al.
    • alloantibodies in kidney graft transplantation. Hum Immunol 2010;
    • 71:857-60. [25] Arnold ML, Dechant M, Doxiadis II, Spriewald BM. Prevalence and specificity
    • HLA alloantibodies in retransplant candidates. Tissue Antigens 2008;
    • 72:60-6. [26] Arnold ML, Heinemann FM, Horn P, Ziemann M, Lachmann N, Muhlbacher A,
    • et al. 16(th) IHIW: anti-HLA alloantibodies of the of IgA isotype in re-
    • transplant candidates. Int J Immunogenet 2013;40:17-20. [27] Arnold ML, Zacher T, Dechant M, Kalden JR, Doxiadis II, Spriewald BM.
    • alloantibodies. Hum Immunol 2004;65:1288-96. [28] Heinemann FM, Roth I, Rebmann V, Arnold ML, Spriewald BM, Grosse-Wilde H.
    • Clin Transpl 2006;16:371-8. [29] Heinemann FM, Roth I, Rebmann V, Arnold ML, Witzke O, Wilde B, et al.
    • 2007;68:500-6. [30] Lowe D, Higgins R, Zehnder D, Briggs DC. Significant IgG subclass
    • prognosis, and the rejection response. Hum Immunol 2013;74:666-72. [31] Crew RJ, Ratner LE. ABO-incompatible kidney transplantation: current practice
    • and the decade ahead. Curr Opin Organ Transplant 2010;15:526-30. [32] Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, et al.
    • Med 2011;365:318-26. [33] Rydberg L, Bengtsson A, Samuelsson O, Nilsson K, Breimer ME. In vitro
    • attached to sepharose. Transpl Int 2005;17:666-72. [34] Tomonari A, Takahashi S, Ooi J, Tsukada N, Konuma T, Kobayashi T, et al.
    • Japan. Bone Marrow Transplant 2007;40:523-8. [35] Valli PV, Fehr T, Puga Yung G, Schulz-Huotari C, Kaup N, Gungor T, et al.
    • ABO-incompatible kidney transplantation. Am J Transplant 2009;9:1072-80. [36] Warren DS, Montgomery RA. Incompatible kidney transplantation: lessons
    • 2010;47:257-64. 1. Locke JE, Zachary AA, Warren DS, Segev DL, Houp JA, et al. (2009)
    • strength of HLA-specific antibody. Am J Transplant Sep; (9): 2136-9. 2. Aiello FB, Calabrese F, Rigotti P, Furian L, Marino S, et al. (2004) Acute
    • Mod Pathol. Feb; 17(2): 189-96. 3. Forman JP, Tolkoff-Rubin N, Pascual M, Lin J (2004) Hepatitis C, acute
    • humoral rejection, and renal allograft survival. J Am Soc Nephrol. Dec; 15(12):
    • 3249-55. 4. Morris PJ, Monaco AP (2004) Antibody revisited. Transplantation; 78: 179-80. 5. Shimmura H, Tanabe K, Ishida H, Tokumoto T, Ishikawa N, et al. (2005) Lack
    • Transplantation. Oct 15; 80(7): 985-8. 6. Tanabe K, Tokumoto T, Ishida H, Toma H, Nakajima I, et al. (2003) ABO-
    • Clinical Transplants, Cecka and Tersaki, 175-181. 7. Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, et al. (2006) C4d
    • and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts:
    • correlation with histologic findings. Am J Transplant: 6: 1829-40. 8. Tyden G, Kumlien G, Genberg H, Sandberg J, Lundgren T, et al. (2005) ABO
    • specific immunoadosprtion and rituximab. Am J Transplant; 5: 145-8. 9. Higgins R, Lowe D, Hathaway M, Lam FT, Kashi H, et al. (2009) Rises and falls
    • incompatible transplantation. Transplantation. Mar 27; 87(6): 882-8. 10. Briggs D, Zehnder D, Higgins RM (2009) Development of non-donor-specific
    • tions. Contrib Nephrol.; 162: 107-16. 11. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, et al. (2010) Banff '09
    • Banff Working Groups American Journal of Transplantation March Volume 10,
    • Issue 3, pages 464-471. 12. Collins AB, Schneeberger EE, Pascual MA, Saidman SL, Williams WW, et al.
    • (1999) Complement activation in acute humoral renal allograft rejection:
    • Diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc
    • Nephrol; 10: 2208-2214. 13. Monteiro F, Rodrigues H, Kalil J, Castro MC, Panajotopoulos N, et al. (2012)
    • Proc. Oct; 44(8): 2411-2. 14. Krishnan NS, Fleetwood P, Higgins RM, Hathway M, Zehnder D, et al. (2008)
    • kidney transplantation. Transplantation. Aug 15; 86(3): 474-7. 15. Burgess C, Mitchell N, Perry KR (2009) Evaluation report: Evaluation of six
    • 1317133422489. 16. Tuder RM, Weinberg A, Panajotopoulos N, Kalil J (1994) Cytomegalovirus
    • cultured human endothelial cells. J Heart Lung Transplant. Jan-Feb; 13(1 Pt 1):
    • 129-38. 17. Di Genova G, Roddick J, McNicholl F, Stevenson FK (2006) Vaccination of
    • antibody production remains vaccine specific Blood. Apr 1; 107(7): 2806-13. 18. Candon S, Thervet E, Lebon P, Suberbielle C, Zuber J, et al. (2009) Humoral
    • recipients. Am J Transplant. Oct; 9(10): 2346-54. 19. Avery RK, Michaels M (2008) Update on immunizations in solid organ
    • transplant recipients: what clinicians need to know. Am J Transplant. Jan; 8(1):
    • 9-14. 20. Vilchez RA, McCurry K, Dauber J, Lacono A, Griffith B, et al. (2002) Influenza
    • 2(3): 287-91. 21. Adams AB, Pearson TC, Larsen CP (2003) Heterologous immunity: an
    • overlooked barrier to tolerance. Immunol Rev. Dec; 196: 147-60. Review. 22. Roddy M, Clemente M, Poggio ED, Bukowski R, Thakkar S, et al. (2005)
    • tion. Transplantation. Aug 15; 80(3): 297-302. 23. Bernasconi NL, Traggiai E, Lanzavecchia A (2002) Maintenance of serological
    • memory by polyclonal activation of human memory B cells. Science. Dec 13;
    • 298(5601): 2199-202. 24. Katerinis I, Hadaya K, Duquesnoy R, Ferrari-Lacraz S, Meier S, et al. (2011)
    • De novo anti-HLA antibody after pandemic H1N1 and seasonal influenza
    • immunization in kidney transplant recipients. Am J Transplant. Aug; 11(8):
    • 1727-33. 25. Amanna IJ, Carlson NE, Slifka MK (2007) Duration of humoral immunity to
    • common viral and vaccine antigens. N Engl J Med; 357: 1903-1915. 26. Zachary AA, Montgomery RA, Ratner LE, Samaniego-Picota M, Haas M, et al.
    • (2003) Specific and durable elimination of antibody to donor HLA antigens in
    • renal-transplant patients. Transplantation. Nov 27; 76(10): 1519-25. 27. Rentenaar RJ, van Diepen FN, Meijer RT, Surachno S, Wilmink JM, et al.
    • (2002) Immune responsiveness in renal transplant recipients: mycophenolic acid
    • severely depresses humoral immunity in vivo. Kidney Int. Jul; 62(1): 319-28.
    • mately 30% of those waiting for a deceased donor transplant
    • The transplants in this study were funded by the National Health Service. The authors have no conflicts of interest to disclose. 1 Transplant Unit, University Hospitals Coventry and Warwickshire, Cov-
    • entry, West Midlands, United Kingdom. 2 Histocompatibility Laboratory, National Blood and Transplant, Birming-
    • ham, West Midlands, United Kingdom. 3 Clinical Sciences Research Institute, Warwick Medical School, University
    • of Warwick, Coventry, West Midlands, United Kingdom. 4 Address correspondence to: Robert Higgins, M.D., Renal Unit, University
    • Hospital, Coventry CV2 2DX, United Kingdom. E-mail:
    • ratory analysis, study design, and writing the manuscript. 1. Palmer A, Taube D, Welsh K, et al. Removal of anti-HLA antibodies by
    • Lancet 1989; 1: 10. 2. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and
    • planted into cross-match-positive recipients. Transplantation 2000; 70:
    • 887. 3. Higgins RM, Bevan DJ, Carey BS, et al. Prevention of hyperacute rejec-
    • plantation. Lancet 1996; 348: 1208. 4. Montgomery RA, Hardy MA, Jordan SC, et al. Consensus opinion from
    • cols. Transplantation 2004; 78: 181. 5. Higgins R, Briggs D, Clarke B, et al. Antibody incompatible transplantation.
    • The British Transplantation Society 2006. Available at: www.bts.org.uk. Ac-
    • cessed July 2011. 6. Higgins RM, Hudson A, Johnson RJ, et al. UK registry of antibody
    • incompatible transplantation 2001-2010. Transplantation 2010;
    • 90(suppl 2S): 189. 7. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immu-
    • disease: Report of the NIH IG02 trial. J Am Soc Nephrol 2004; 15: 3256. 8. Gupta A, Iveson V, Varagunam M, et al. Pretransplant donor-specific
    • vant? Transplantation 2008; 85: 1200. 9. Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA
    • rol 2010; 21: 1398. 10. Singh N, Djamali A, Lorentzen D, et al. Pretransplant donor-specific
    • ated with inferior kidney transplant outcomes. Transplantation 2010;
    • 90: 1079. 11. Ba¨chler K, Amico P, Ho¨nger G, et al. Efficacy of induction therapy with
    • nor-specific HLA antibodies. Am J Transplant 2010; 10: 1254. 12. Willicombe M, Brookes P, Santos-Nunez E, et al. Outcome of patients
    • duction and tacrolimus monotherapy. Am J Transplant 2011; 11: 470. 13. Stegall MD, Gloor J, Winters JL, et al. A comparison of plasmapheresis
    • high levels of donor specific alloantibody. Am J Transplant 2006; 6: 346. 14. Gloor JM, Winters JL, Cornell LD, et al. Baseline donor-specific anti-
    • tion. Am J Transplant 2010; 10: 582. 15. Haririan A, Nogueira J, Kukuruga D, et al. Positive cross-match living
    • plant 2009; 9: 536. 16. West-Thiekle P, Herren H, Thiekle J, et al. Results of positive cross-
    • Am J Transplant 2008; 8: 348. 17. Aklain E, Dinavahi R, Friedlander R, et al. Addition of plasmapheresis
    • Nephrol 2008; 3: 1160. 18. Thirkle JJ, West-Theikle PM, Herren HL, et al. Living donor kidney
    • Chicago experience. Transplantation 2009; 87: 268. 19. Mai ML, Ahsan N, Wadei HM, et al. Excellent renal allograft survival in
    • tation 2009; 87: 227. 20. Higgins R, Zehnder D, Chen K, et al. The histological development of
    • nal transplantation. Nephrol Dial Transplant 2010; 25: 1306. 21. Kosmoliaptsis V, O'Rourke C, Bradley JA, et al. Improved Luminex-
    • thiothreitol-treated sera. Hum Immunol 2010; 71: 45. 22. Higgins R, Lowe D, Hathaway M, et al. Double filtration plasmaphere-
    • 2010; 14: 392. 23. Higgins R, Lowe D, Hathaway M, et al. Rises and falls in donor-specific
    • transplantation. Transplantation 2009; 87: 882. 24. Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin
    • awaiting kidney transplantation. Transplantation 2010; 89: 1095. 25. Higgins R, Hathaway M, Lowe D, et al. Blood levels of donor-specific
    • body. Transplantation 2007; 84: 876.
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
    73
    73%
  • Discovered through pilot similarity algorithms. Send us your feedback.

Share - Bookmark

Cite this article