Background: CD56+ and CD163+ cell infiltration in human kidney transplant biopsies have not been fully evaluated. Methods: We investigated the association of CD56+ and CD163+ cell infiltration with human kidney transplant biopsies with antibody- or T-cell-mediated rejection (TCMR) and other histologic lesions. One hundred and seventy four clinically indicated transplant biopsies were included in this analysis. Immunohistochemical staining for C4d, CD56 and CD163 was performed. Results: One hundred and seventy four indication biopsies were divided into early (≤1 year posttransplant; n = 49) and late (>1 year posttransplant; n = 125) biopsies. High numbers of CD56+ cells were uncommon in early biopsies except for those with antibody-mediated rejection (AMR) only. On the other hand, high numbers of CD56+ cells were observed in late biopsies diagnosed as TCMR only, AMR only, and TCMR combined with AMR. In early biopsies, both CD56+ and CD163+ infiltrates correlated strongly with interstitial inflammation, tubulitis, and peritubular capillaritis (ptc) scores. The ci and ct scores, however, were correlated only with the number of CD56+ cells. In late biopsies, on the other hand, the number of CD56+ infiltrates was correlated only with ptc, while the number of CD163+ infiltrates was weakly correlated with any histologic lesion. Multivariable analyses showed that chronic active AMR and the number of CD56+ cells/10 HPF were independently associated with death-censored graft failure post-biopsy. The number of CD163+ cells was not correlated with any pathologic lesion and post-biopsy graft failure. CD56+ infiltrates were also associated with interstitial fibrosis and tubular atrophy. Conclusions: Intragraft CD56+ cell infiltrates were significantly associated with AMR and subsequent poor clinical outcomes.

Keywords:
CD56, CD163, Transplant biopsies, Graft survival, Graft function
1.
Wilkinson A: The ‘First quarter': the first three months after transplantation; in Danovitch GM (ed): Handbook of Kidney Transplantation, ed 5. Philadelphia, USA, Lippincott Williams & Wilkins, 2009, p 213.
2.
Kotrych K, Masiuk M, Domański l, Rózański J, Droździk M: Peripheral blood lymphocytes P-glycoprotein (P-gp, gp-170) expression in allogenic kidney transplant patients. Nephrology (Carlton) 2006;11:257-260.
3.
Hamerman JA, Ogasawara K, Lanier LL: NK cells in innate immunity. Curr Opin Immunol 2005;17:29-35.
4.
Caligiuri MA: Human natural killer cells. Blood 2008;112:461-469.
5.
Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L: What is a natural killer cell? Nat Immunol 2002;3:6-8.
6.
Chiorean EG, Miller JS: The biology of natural killer cells and implications for therapy of human disease. J Hematother Stem Cell Res 2001;10:451-463.
7.
Kowal K, Moniuszko M, Bodzenta-Lukaszyk A: The effect of inhaled corticosteroids on the concentration of soluble CD163 in induced sputum of allergic asthma patients. J Investig Allergol Clin Immunol 2014;24:49-55.
8.
Fildes JE, Yonan N, Tunstall K, Walker AH, Griffiths-Davies L, et al: Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation. J Heart Lung Transplant 2008;27:203-207.
9.
Kitchens WH, Uehara S, Chase CM, Colvin RB, Russell PS, et al: The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation 2006;81:811-817.
10.
Meehan AC, Sullivan LC, Mifsud NA, Brooks AG, Snell GI, et al: Natural killer cell activation in the lung allograft early posttransplantation. Transplantation 2010;89:756-763.
11.
Guillén-Gómez E, Guirado L, Belmonte X, Maderuelo A, Santín S, et al: Monocyte implication in renal allograft dysfunction. Clin Exp Immunol 2014;175:323-331.
12.
Solez K, Colvin RB, Racusen LC, Haas M, Sis B, et al: Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8:753-760.
13.
Nemlander A, Saksela E, Häyry P: Are ‘natural killer' cells involved in allograft rejection? Eur J Immunol 1983;13:348-350.
14.
Blancho G, Buzelin F, Dantal J, Hourmant M, Cantarovich D, et al: Evidence that early acute renal failure may be mediated by CD3- CD16+ cells in a kidney graft recipient with large granular lymphocyte proliferation. Transplantation 1992;53:1242-1247.
15.
Hadad U, Martinez O, Krams SM: NK cells after transplantation: friend or foe. Immunol Res 2014;58:259-267.
16.
Kummer JA, Wever PC, Kamp AM, ten Berge IJ, Hack CE, Weening JJ: Expression of granzyme A and B proteins by cytotoxic lymphocytes involved in acute renal allograft rejection. Kidney Int 1995;47:70-77.
17.
Kondo T, Morita K, Watarai Y, Auerbach MB, Taub DD, et al: Early increased chemokine expression and production in murine allogeneic skin grafts is mediated by natural killer cells. Transplantation 2000;69:969-977.
18.
Hancock WW, Gao W, Faia KL, Csizmadia V: Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000;12:511-516.
19.
Bachetoni A, Lionetti P, Cinti P, Alò P, Molajoni ER, et al: Homing of CD4+CD56+ T lymphocytes into kidney allografts during tubular necrosis or rejection. Clin Transplant 1995;9:433-437.
20.
Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, et al: NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant 2010;10:1812-1822.
21.
Sellarés J, Reeve J, Loupy A, Mengel M, Sis B, et al: Molecular diagnosis of antibody-mediated rejection in human kidney transplants. Am J Transplant 2013;13:971-983.
22.
Hayde N, Bao Y, Pullman J, Ye B, Calder RB, et al: The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol 2013;8:2141-2148.
23.
Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran PF: Interpreting NK cell transcripts versus T cell transcripts in renal transplant biopsies. Am J Transplant 2012;12:1180-1191.
24.
Scian MJ, Maluf DG, Archer KJ, Suh JL, Massey D, et al: Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy: diagnosis versus prediction. Transplantation 2011;91:657-665.
25.
Notas G, Kisseleva T, Brenner D: NK and NKT cells in liver injury and fibrosis. Clin Immunol 2009;130:16-26.
26.
Harada M, Seino K, Wakao H, Sakata S, Ishizuka Y, et al: Down-regulation of the invariant valpha14 antigen receptor in NKT cells upon activation. Int Immunol 2004;16:241-247.
27.
Eberl G, MacDonald HR: Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 1998;9:345-353.
28.
Venkataswamy MM, Porcelli SA: Lipid and glycolipid antigens of CD1d-restricted natural killer T cells. Semin Immunol 2010;22:68-78.
29.
Obara H, Nagasaki K, Hsieh CL, Ogura Y, Esquivel CO, et al: IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant 2005;5:2094-2103.
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2015
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