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Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty.

Hallab NJ, Caicedo M, Finnegan A, Jacobs JJ - J Orthop Surg Res (2008)

Bottom Line: Of the 15 metal ion-challenged subjects with well functioning total hip arthroplasties, 7 demonstrated a proliferative response to Chromium, Nickel, Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive.Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM).Th2) type response is likely associated with any metal induced reactivity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA. nhallab@rush.edu

ABSTRACT

Background: All prostheses with metallic components release metal debris that can potentially activate the immune system. However, implant-related metal hyper-reactivity has not been well characterized. In this study, we hypothesized that adaptive immunity reaction(s), particularly T-helper type 1 (Th1) responses, will be dominant in any metal-reactivity responses of patients with total joint replacements (TJAs). We tested this hypothesis by evaluating lymphocyte reactivity to metal "ions" in subjects with and without total hip replacements, using proliferation assays and cytokine analysis.

Methods: Lymphocytes from young healthy individuals without an implant or a history of metal allergy (Group 1: n = 8) were used to assess lymphocyte responses to metal challenge agents. In addition, individuals (Group 2: n = 15) with well functioning total hip arthroplasties (average Harris Hip Score = 91, average time in-situ 158 months) were studied. Age matched controls with no implants were also used for comparison (Group 3, n = 8, 4 male, 4 female average age 70, range 49-80). Group 1 subjects' lymphocyte proliferation response to Aluminum+3, Cobalt+2, Chromium+3, Copper+2, Iron+3, Molybdenum+5, Manganeese+2, Nickel+2, Vanadium+3 and Sodium+2 chloride solutions at a variety of concentrations (0.0, 0.05, 0.1, 0.5, 1.0 and 10.0 mM) was studied to establish toxicity thresholds. Mononuclear cells from Group 2 and 3 subjects were challenged with 0.1 mM CrCl3, 0.1 mM NiCl2, 0.1 mM CoCl2 and approx. 0.001 mM titanium and the reactions measured with proliferation assays and cytokine analysis to determine T-cell subtype prominence.

Results: Primary lymphocytes from patients with well functioning total hip replacements demonstrated a higher incidence and greater magnitude of reactivity to chromium than young healthy controls (p < 0.03). Of the 15 metal ion-challenged subjects with well functioning total hip arthroplasties, 7 demonstrated a proliferative response to Chromium, Nickel, Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive. Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM). The differential secretion of signature T-cell subsets' cytokines (Th1 and Th2 lymphocytes releasing IFN-gamma and IL-4, respectively) between those total hip arthroplasty subjects which demonstrated metal-reactivity and those that did not, indicated a Th1 type (IFN-gamma) pro-inflammatory response.

Conclusion: Elevated proliferation and production of IFN-gamma to metals in hip arthroplasty subjects' lymphocytes indicates that a Th1 (vs. Th2) type response is likely associated with any metal induced reactivity. The involvement of an elevated and specific lymphocyte response suggests an adaptive (macrophage recruiting) immunity response to metallic implant debris rather than an innate (nonspecific) immune response.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of the inflammatory and peri-implant cytokine release cascade associated with activation of Th1 lymphocytes, and the inhibitory effects on bone function.
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Figure 6: Schematic diagram of the inflammatory and peri-implant cytokine release cascade associated with activation of Th1 lymphocytes, and the inhibitory effects on bone function.

Mentions: When combined, the release of cytokines IFN-gamma and IL-2 by lymphocytes can induce macrophage production of TNF-α which can establish an autocrine stimulatory loop required for continued macrophage activation and recruitment. [43-47] Therefore the present study demonstrates likely mechanisms by which lymphocyte mediated metal reactivity may contribute to the etiology of macrophage- and particle-induced osteolysis (Figure 6). IFN-gamma released by metal-activated Th1 lymphocytes is also important to macrophage activation because it is necessary for TNF-alpha released from macrophages to synergize with IFN-gamma in an autocrine fashion to induce a variety of macrophage activation genes including nitric oxide synthase, also implicated in aseptic osteolysis. [37,48] Therefore, it may be less important that a Th1 or Th2 paradigm has been determined by cytokine profiling and more important that certain cytokines themselves have been identified especially in the context of recent reports where the identification of discrete T-helper cell populations seem to be constantly updated and revised. [23]


Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty.

Hallab NJ, Caicedo M, Finnegan A, Jacobs JJ - J Orthop Surg Res (2008)

Schematic diagram of the inflammatory and peri-implant cytokine release cascade associated with activation of Th1 lymphocytes, and the inhibitory effects on bone function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2275232&req=5

Figure 6: Schematic diagram of the inflammatory and peri-implant cytokine release cascade associated with activation of Th1 lymphocytes, and the inhibitory effects on bone function.
Mentions: When combined, the release of cytokines IFN-gamma and IL-2 by lymphocytes can induce macrophage production of TNF-α which can establish an autocrine stimulatory loop required for continued macrophage activation and recruitment. [43-47] Therefore the present study demonstrates likely mechanisms by which lymphocyte mediated metal reactivity may contribute to the etiology of macrophage- and particle-induced osteolysis (Figure 6). IFN-gamma released by metal-activated Th1 lymphocytes is also important to macrophage activation because it is necessary for TNF-alpha released from macrophages to synergize with IFN-gamma in an autocrine fashion to induce a variety of macrophage activation genes including nitric oxide synthase, also implicated in aseptic osteolysis. [37,48] Therefore, it may be less important that a Th1 or Th2 paradigm has been determined by cytokine profiling and more important that certain cytokines themselves have been identified especially in the context of recent reports where the identification of discrete T-helper cell populations seem to be constantly updated and revised. [23]

Bottom Line: Of the 15 metal ion-challenged subjects with well functioning total hip arthroplasties, 7 demonstrated a proliferative response to Chromium, Nickel, Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive.Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM).Th2) type response is likely associated with any metal induced reactivity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA. nhallab@rush.edu

ABSTRACT

Background: All prostheses with metallic components release metal debris that can potentially activate the immune system. However, implant-related metal hyper-reactivity has not been well characterized. In this study, we hypothesized that adaptive immunity reaction(s), particularly T-helper type 1 (Th1) responses, will be dominant in any metal-reactivity responses of patients with total joint replacements (TJAs). We tested this hypothesis by evaluating lymphocyte reactivity to metal "ions" in subjects with and without total hip replacements, using proliferation assays and cytokine analysis.

Methods: Lymphocytes from young healthy individuals without an implant or a history of metal allergy (Group 1: n = 8) were used to assess lymphocyte responses to metal challenge agents. In addition, individuals (Group 2: n = 15) with well functioning total hip arthroplasties (average Harris Hip Score = 91, average time in-situ 158 months) were studied. Age matched controls with no implants were also used for comparison (Group 3, n = 8, 4 male, 4 female average age 70, range 49-80). Group 1 subjects' lymphocyte proliferation response to Aluminum+3, Cobalt+2, Chromium+3, Copper+2, Iron+3, Molybdenum+5, Manganeese+2, Nickel+2, Vanadium+3 and Sodium+2 chloride solutions at a variety of concentrations (0.0, 0.05, 0.1, 0.5, 1.0 and 10.0 mM) was studied to establish toxicity thresholds. Mononuclear cells from Group 2 and 3 subjects were challenged with 0.1 mM CrCl3, 0.1 mM NiCl2, 0.1 mM CoCl2 and approx. 0.001 mM titanium and the reactions measured with proliferation assays and cytokine analysis to determine T-cell subtype prominence.

Results: Primary lymphocytes from patients with well functioning total hip replacements demonstrated a higher incidence and greater magnitude of reactivity to chromium than young healthy controls (p < 0.03). Of the 15 metal ion-challenged subjects with well functioning total hip arthroplasties, 7 demonstrated a proliferative response to Chromium, Nickel, Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive. Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM). The differential secretion of signature T-cell subsets' cytokines (Th1 and Th2 lymphocytes releasing IFN-gamma and IL-4, respectively) between those total hip arthroplasty subjects which demonstrated metal-reactivity and those that did not, indicated a Th1 type (IFN-gamma) pro-inflammatory response.

Conclusion: Elevated proliferation and production of IFN-gamma to metals in hip arthroplasty subjects' lymphocytes indicates that a Th1 (vs. Th2) type response is likely associated with any metal induced reactivity. The involvement of an elevated and specific lymphocyte response suggests an adaptive (macrophage recruiting) immunity response to metallic implant debris rather than an innate (nonspecific) immune response.

No MeSH data available.


Related in: MedlinePlus