In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.

Adhesion Molecules as Markers of Acute Cellular Rejection of Renal Allografts

Luan D. Truong*, M.D., Scott B. Shappell*, M.D., Ph.D.,
and Kim Solez•, M.D.

Department of Pathology, The Methodist Hospital*, Baylor College of Medicine*, Houston, Texas, and The University of Alberta•, Faculty of Medicine, Edmonton, Canada.

 

 

Address reprint requests to:	Luan D. Truong, M.D.
				Dept. of Pathology, M.S. 205
				The Methodist Hospital
				Houston, TX 77030 USA

INTRODUCTION.

Acute rejection of renal transplants involves many interrelated processes, including recognition of alloantigens, activation and proliferation of allospecific T cells, recruitment, interaction, and migration of effector inflammatory cells, all resulting in target cell damage by cytolytic or delayed hypersensitivity mechanism [1-5]. Recently, it has become increasingly known that various adhesion molecules play pivotal roles in the above processes [1-5]. Indeed, treatment with antibodies against several adhesion molecules can reverse or even prevent acute rejection [2, 6-9]. This communication will briefly review the functional significance and the diagnostic utility of adhesion molecule expression in acute renal transplant rejection.

 

FUNCTIONAL SIGNIFICANCE OF ADHESION MOLECULES IN TRANSPLANT REJECTION.

The adhesion molecules mediating various processes in acute rejection are summarized in Tables 1-5. It should be noted that many adhesion molecules are expressed by several cell types and thus may mediate more than one function [1-5]. Although numerous synonyms exist for some adhesion molecules, only the most recent and widely accepted names and abbreviations are used herein [1-5, 10].

Antigen presentation: It is well known that specific recognition of the alloantigen-MHC complex on antigen presenting cells by the T cell receptor-CD4 (or CD8) complex results in activation of T lymphocytes only if secondary stimulatory signals are provided by additional contacts between antigen presenting cells and T cells [1, 11]. This accessory stimulatory contact is provided by the pairs of adhesion molecules listed in Table 1 [1-5]. Aside from the dendritic reticulum cells ("professional" antigen presenting cells), any cell with constitutive or induced expression of MHC molecules may assume this function. However, whether the antigen presentation results in activation of allospecific T-cells depends on whether antigen presenting cells express the appropriate adhesion molecules for secondary signalling [11].

Inflammatory Cell-Endothelial Cell Interactions: During acute rejection, inflammatory cells, including T lymphocytes, must come in contact with endothelial cells, which not only present alloantigens and are, themselves, targets for immune-mediated injury, but also constitute a barrier through which inflammatory cells must transmigrate in order to localize in the renal interstitium [1-5]. The necessary contact is mediated by the pairs of adhesion molecules listed in Table 2. Interactions of VLA-4/VCAM-1 and LFA-1/ICAM-1 are of indisputable importance in acute rejection and have been thoroughly evaluated in the tissue diagnosis of rejection [12-14]. Although other adhesion/ligand pairs play crucial roles in inflammation, whether they facilitate acute rejection or whether their identification in tissue sections has a diagnostic role remains unclear [1-5, 11-14].

Transendothelial migration of inflammatory cells: Allospecific or non-specific inflammatory cells must migrate through capillaries to infiltrate the interstitium, a hallmark of acute cellular rejection. This highly complex process likely depends on the interplay of many factors, including cytokines, chemotactic factors, and adhesion molecules [15, 16]. The role of specific adhesion molecules in this process has been partly elucidated [1, 15, 16]. LFA-1/ICAM-1 interaction appears crucial to this process Table 3, as T cell clones from LFA-1 deficient individuals bind normally to cultured endothelial monolayers, but migrate through cultured endothelial cells at only about half the rate of normal lymphocytes [17]. In addition, monoclonal antibodies against LFA-1 markedly reduce lymphocyte migration [18].

Interstitial localization of inflammatory cells: (Table 4) The dynamics of inflammatory cells in the renal interstitium are poorly understood. The role of adhesion molecules in this process is mostly conjectural, based on knowledge of adhesion molecules expressed by inflammatory cells and their ligands found in some native interstitial cells, but ubiquitously on extracellular matrix proteins. For example; LFA-1 on T-lymphocytes can bind to ICAM-1 induced on interstitial fibroblast-like cells during rejection. VLA-4 and VLA-5 on activated T cells can bind fibronectin, and VLA-1, VLA-2, VLA-3, VLA-5, and VLA-6 may bind various other extracellular matrix proteins, including collagens and laminin [10].

Binding of cytotoxic T-cells and natural killer cells to target cells: Effector cells mediate damage to the rejected kidney through many mechanisms, one of which is lysis of target cells by CD8+ T lymphocytes or natural killer cells. Cell to cell contact, which may be provided by the pairs of adhesion molecules listed in Table 5, is necessary for these cells to deliver the "cytolytic hit" [20]. These specific adhesion molecule interactions may explain, at least in part, the attachment of CD8 T cells to activated endothelial cells in producing endothelialitis and the infiltration of these lymphocytes between tubular epithelial cells with resultant tubulitis, both of which are characteristically seen in acute rejection [21].

Several studies have reported prevention or reversal of acute rejection in animals or humans by treatment with antibodies against various adhesion molecules, including ICAM-1 and LFA-1. These fascinating observations confirm the crucial role of adhesion molecules in the diverse biological processes leading to acute rejection [6-9].

 

DIAGNOSTIC UTILITY OF ADHESION MOLECULE EXPRESSION IN ALLOGRAFT REJECTION.

Although numerous adhesion molecules are implicated in acute rejection, only a few of them have been evaluated for diagnostic use. Most thoroughly studied are ICAM-1 and VCAM-1, whereas significantly less information is available for E-selectin, P-selectin, and PECAM-1. The diagnostic use of these molecules centers around their immunohistochemical detection in graft biopsies. Rare studies have supplemented immunohistochemical analysis with in situ hybridization [12, 22]. Studies analyzing the corresponding mRNAs by Northern hybridization or polymerase chain reaction have not been attempted and likely would not have the same diagnostic utility since changes in message level would not be site specific. As implied above, some adhesion molecules are expressed by multiple cell types (e.g., ICAM-1 on monocytes, mesangial cells, lymphocytes, endothelial cells, tubular epithelial cells), some of which may have upregulated expression in disease processes other than rejection, which can affect the transplanted kidney. It is the change in expression of these molecules at specific renal compartments that provide the diagnostic clues. This information is best provided by immunohistochemistry. Staining patterns with monoclonal antibodies to the various pertinent adhesion molecules in the normal kidney and renal allograft with rejection are outlined in Table 6.

ICAM-1: All studies agree that ICAM-1 is strongly expressed constitutively in endothelial cells of the normal kidney, and is not phenotypically altered during acute rejection [12-14, 23-28]. In contrast, the normal tubules are either completely negative or display weak staining of rare proximal tubules in up to 65% of cases. Acute rejection is associated with diffuse staining of proximal tubules and focal staining of distal tubules and collecting ducts. The diagnostic utility of ICAM-1 expression is somewhat lessened since biopsies of grafts without rejection or grafts with stable function also sporadically express increased tubular ICAM-1 [25, 26]. Nevertheless, staining for ICAM-1 has been used for differentiating acute rejection from cyclosporin - A nephrotoxicity [29].

VCAM-1: The glomerular endothelial cells in normal kidney do not express VCAM-1 and remain negative in acute rejection [22, 24-26, 30, 31]. In contrast, the endothelial cells of intertubular capillaries or large vessels display negative or very weak, focal staining in normal kidney, but become strongly and diffusely positive during acute rejection. The changes of tubular VCAM-1 expression in acute rejection are similar to that of ICAM-1. Some preliminary reports indicate overlapping patterns of VCAM-1 staining between rejecting and stable grafts [25, 26].

E-selectin: Expression of E-selectin is not seen in normal kidney, but is observed focally in endothelium of intertubular capillaries and large vessels during rejection [13, 14, 24-26].

P-selectin: P-selectin appears to be focally expressed in endothelial cells of normal kidneys and is not detectably altered during acute rejection [26].

PECAM-1: Immunohistochemical staining for this adhesion molecule strongly decorates all endothelial cells in normal kidney. During acute rejection, up to 17% of cases paradoxically display focal loss of staining, which may be related to endothelial damage [14]. Another preliminary study, however, indicated increased PECAM-1 staining in acute rejection [13].

 

CONCLUSION

The study of adhesion molecules not only provides significant insight into the mechanisms leading to acute renal allograft rejection, but also opens new venues for therapeutic manipulation. Although acute rejection is frequently associated with distinctive changes in the tissue expression of several adhesion molecules, the precise role of these changes in the differential diagnosis of acute rejection awaits further studies.

 

References

  1. Kirby JA, Wilson JL: Transplant Rev 8: 114, 1994.

     

  2. Brady HR: Kidney Int 45: 1285, 1994.

     

  3. Brujin JA, Heer ED: Lab Invest 72: 387, 1995.

     

  4. Rabb HAA: Am J Kidney Dis 23:155, 1994.

     

  5. Stamenkovic I: in Colvin RB, Bhan AK, McClusky RT (eds): Diagnostic Immunopathology, Raven Press, New York, 1995, p 61.

     

  6. Le Mauff B, Hourmant M, Le Meur Y, et al: Transplant Proc 27:865, 1995.

     

  7. Cosimi AB, Conti D, Delmonico FL, et al: J. Immunol 144: 4604, 1990.

     

  8. Jendrisak G, Gamero J, Mohanakumar T, et al: Transplant Proc 25:828, 1993.

     

  9. Miwa S, Kawasaki S, Makuuchi M, et al: Transplant Proc 27:111, 1995.

     

  10. Abelda SM, Buck CA: FASEB J. 4:2868, 1990.

     

  11. Wilson JL, Proud G, Forsyth JL, et al: Transplantation 59:91, 1995.

     

  12. Sugito K, Morozumi K, Koide M, et al: Transplant Proc 27:991, 1995.

     

  13. vonWillebrand E, Krogerus L, Samela K, et al: Transplant Proc:917, 1995.

     

  14. Fuggle SV, Sanderson JB, Gray DW, et al: Transplantation 55:117, 1993.

     

  15. Furie MB, Randolph GJ: Am. J. Pathol. 146:1287,1995.

     

  16. Hill PA, Lan HY, Nikolic-Paterson, et al: Kidney Int 45:32, 1994.

     

  17. Kavanaugh AI, Lightfoot E, Lipsky PE, et al: J Immunol 146:4149, 1991.

     

  18. van Epps DE, Potter J, Vachula M, et al: J Immunol. 143:3207, 1989.

     

  19. Ruoslahti E, Noble NA, Kagami S, et al: Kidney Int 45, Supp 44:S17, 1994.

     

  20. Storkus WJ, Dawson JR: Crit Rev Immunol 10:393, 1991.

     

  21. Solez K, Axelson RA, Benediktsson et al: Kidney Int 44:411, 1993.

     

  22. Alpers LE, Hudkin KL, Davis CL, et al: Kidney Int 44:805, 1993.

     

  23. Moolenaar W, Brujin JA, Schrama E, et al: Transplant Int 4:140, 1991.

     

  24. Brockmeyer C, Ulbrecht M, Schendel DJ, et al: Transplantation 55:610, 1993.

     

  25. Thervet E, Patey N, Legendre CL, et al: Transplant Proc 27:1007, 1995.

     

  26. Anderson CB, Lodefoged SD, Larsen S: APMIS 102: 23, 1994.

     

  27. Faull RJ, Russ GR: Transplantation 48:226, 1990.

     

  28. Bishop GA, Hall BM: Kidney Int 36:1078, 1989.

     

  29. Mampaso F, Sanchez-Madrid F, Marcen R, et al: Transplantation 56:687, 1993.

     

  30. Briscoe DM, Pober JS, Harmon WE, et al: J Am Soc Neprol 3:1180, 1992.

     

  31. Lin Y, Kirby JA, Browell DA, et al: Clin Exp Immunol 92:145, 1993.

Return to Banff Presentations

 


Last Modified: April 03, 1996 9:21:37 AM