A study of tissue interface membranes from revision accord knee arthroplasty: the role of T lymphocytes
Introduction
Despite four decades of advances in the design of orthopaedic devices, aseptic loosening remains the most common reason for revision of total joint arthroplasty. The periprosthetic bone loss associated with aseptic loosening can be considered to be the result of a macrophage-driven chronic inflammatory response [1], [2], [3].
Detailed histological analysis of interface membranes retrieved during revision surgery has shown macrophages to predominate with giant cells, fibroblasts, granulocytes, neutrophils and also with the T cells present [4], [5], [6], [7]. In addition, these interface membranes have been shown to contain large numbers of prosthesis-derived wear particles [8], [9]. These are thought to stimulate the macrophage-driven inflammatory response which ultimately results in bone resorption and loosening of the prosthesis [10].
Much of the work to date has, therefore, focused on macrophages within this tissue and their capacity to release many of the inflammatory mediators necessary to perpetuate the cycle of inflammation and stimulate bone-resorbing cells. Some studies have shown the proinflammatory cytokines IL-1β, TNF-α and IL-6, known to be important mediators of bone resorption, to be present [11], [12], [13].
T lymphocytes have been observed in all studies but in fewer numbers compared to macrophages. There is speculation around the presence of a hypersensitivity reaction [14] and it has been assumed that the presence of T cells, particularly in association with metal wear particles, is indicative of a hypersensitivity reaction.
Metallosis due to metal wear debris, manifesting as massive staining of tissue surrounding the prosthesis, is frequently observed and there have been reports of dissemination of metal debris in lymph nodes, liver, spleen and urine [15], [16], [17]. Dermal hypersensitivy reactions to nickel and other metal ions are a well-accepted phenomenon with T lymphocytes recognising the metal conjugated to native proteins. However, the presence of hypersensitivity to prosthesis-derived metal wear, measured by the skin patch test, is reported to occur in only 1% of the cases [18]. However, the skin patch test for titanium oxide, used as an indicator of a hypersensitivity reaction, may not reflect the immunological response at the implant site [19]. Reports in the literature of adverse immunological reponses to metal wear particles are rare [20], [21] and generally the evidence shows that metal implants currently in use are immunologically well tolerated [22], [23], [24], [25].
In addition to metal wear, ultra-high molecular weight polyethylene (UHMWPE) and bone cement particles have also been implicated as causative agents of hypersensitivity leading to early failure of prostheses [26]. Investigations into a possible hypersensitivity reaction to components of bone cement have demonstrated positive patch tests to N,N-dimethylparatoluidine (DMT), a cement accelerator, in a small subgroup of patients with early loosening of hip replacements. Interestingly, the same study found no response to polyethylene, to any of the metals or methylmethacrylate [27].
A number of groups have focused on the effects of co-stimulatory molecule interactions (B7-1(CD80):CD28) within tissue from revision hip arthroplasty [28], [29]. CD28 present on T lymphocytes is known to be important in its interaction with CD80 on activated macrophages in producing the stimulus for T-cell activation; however, the identification of CD28 within this tissue cannot be taken as indicative of its participation in an active T-cell response as these molecules are constitutively expressed on resting CD4+ cells [30].
It is clear that further investigation into the role of T lymphocytes at the bone implant interface is necessary to determine whether the adverse immunological reactions observed are, in fact, T-cell driven.
This study of the immunological responses to orthopaedic devices and their resultant metal, polyethylene and bone cement particles is complex and it is further compounded by the comparison of different designs of both hip and knee prostheses in the same study. Focusing on the tissue response around one particular design removes the complication of comparing the response to different metal wear species.
This investigation was carried out on retrieved interface tissue from around the cemented Johnson–Elloy (Accord) total knee arthroplasty (Depuy International Ltd., Leeds, UK). This prosthesis comprises a mobile UHMWPE insert, interposed between nitrogen stainless-steel femoral and tibial components. Survivorship was reported by the designing surgeon to be 97.7% at 80 months [31] and by another hospital as 58% at 10 years [32]. The aim of this study was to combine histological and molecular biological techniques to build a detailed picture of the cell types present in tissue surrounding failed Accord Knee prostheses and to determine the occurrence of inflammatory cells and cytokines which may contribute to implant failure. Immunohistochemistry was used to identify macrophages, T cells, neutrophils, granulocytes, fibroblasts and the protein products of inflammatory cytokines.
The hallmark of T-cell activation is the active production of cytokines in response to antigen recognition. To detect this activation, the reverse transcription polymerase chain reaction (RT-PCR) was employed to detect mRNA for the T cell cytokines IL-2, IFNγ, IL-4, and IL-10. The chemokines MCP-1, MIP-1α and RANTES were also investigated to shed light on the possible mechanism of T-cell extravasation and migration to these implant sites.
Section snippets
Specimens
Twenty-four patients included in the study underwent revision knee arthroplasty for a failed Accord prosthesis. The interface tissue was immediately snap frozen in isopentane over cardice before being transported back to the laboratory. A note was made of the patient's sex, age, the implant duration, mechanical status of the device and the presence of any areas of osteolysis.
Immunohistochemistry
Serial 7 μm thick cryostat sections were cut and placed on 3-aminopropyltriethoxysilane (APTES) coated slides, fixed in
Immunohistochemistry
The average patient age was 73.25 years and the average implant time 7.33 years.
There was considerable variation in total cell numbers, numbers of macrophages and T cells as illustrated by Table 2. Macrophages were the dominant cell type present within the sections, accounting for over half of all cell types.
T cells were observed in all patients although the percentage of cells that expressed the CD3 marker varied between 1% and 42% (average 22%) (Fig. 1). T cells of both the helper and
Discussion
Tissue samples from patients undergoing revision surgery for aseptic loosening were analysed to determine the presence and possible significance of inflammatory cells, cytokines and chemokines present in these prosthesis failures.
This study has also shown that macrophages produce both the inflammatory cytokines and chemokines which may recruit further inflammatory cells to the implant site to perpetuate the cycle. The macrophages sequester a proportion of wear particles but inadequate removal
Conclusion
The pattern of inflammation observed in tissue around failed Accord devices is comparable to other failed devices [48]. The response appears to be macrophage-driven involving many inflammatory cytokines and chemokines that lead to the recruitment of T cells to the implant site. The evidence points to antigen-independent homing of T cells to the implant site and it is probable that the wear particles act as a non-specific inflammatory irritant. The T cells do not appear to participate in a
Acknowledgments
I gratefully acknowledge the support of the NWRHA and the UK Research Councils EPSRC, BBSRC AND MRC for funding through the IRCol in Tissue Engineering.
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