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Ann Thorac Surg 2008;85:1656-1661. doi:10.1016/j.athoracsur.2008.01.050
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Cellular Immunity Impaired Among Patients on Left Ventricular Assist Device for 6 Months

Pam M. Kimball, PhD*, Maureen Flattery, RN, Felecia McDougan, MT, Vigneshwar Kasirajan, MD

Department of Surgery, Virginia Commonwealth University Hospitals, Richmond, Virginia

Accepted for publication January 17, 2008.

* Address correspondence to Dr Kimball, Box 980005, Virginia Commonwealth University Hospitals, Richmond, VA 23298 (Email: pkimball{at}gems.vcu.edu).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Sustained maintenance on left ventricular assist device (LVAD) is associated with an increased frequency of severe infections. Although temporary changes in cellular immunity are seen immediately after implantation, the consequence of sustained LVAD treatment on immunity is unknown.

Methods: In vitro functional and phenotypic markers of T cell activation and 6 month clinical outcome were compared between patients with ≥6-month LVAD therapy and heart failure control patients.

Results: Recipients of LVADs had more infections (45.5% versus 0%; p < 0.05) and mortality (54% versus 16%; p < 0.05) than control patients. T-cell proliferative responses were lower among LVAD recipients than control patients when challenged with phytohemagglutinin (3.4 ± 4.7 versus 28.5 ± 19.6; p < 0.01), anti-CD3 (4.3 ± 4.5 versus 16.4 ± 17; p < 0.01), and staphylococcal enterotoxin B (7.2 ± 6.3 versus 26.1 ± 15.6; p = 0.002). Proliferative hyporesponsiveness among LVAD recipients was not caused by apoptosis (2.6% ± 2.7% versus 2.7% ± 2.1%; p = 0.94) or insufficient CD4+ cells (42.1% ± 11.3% versus 40.2% ± 7.5%; p = 0.71) relative to control patients. Instead, CD3+ cells from LVAD patients expressed less interleukin 2 (2.5% ± 1.5% versus 5.2% ± 3.1%; p = 0.03) and tumor necrosis factor-{alpha} (6.0% ± 3.5% versus 25.8% ± 8.7%; p < 0.001) and more interleukin 10 (5.8% ± 6.1% versus 2.6% ± 2.1%; p < 0.05). In addition, suppressive T-regulatory cells were more prevalent in LVAD patients than control patients (12.9% ± 3.2% versus 1.2% ± 1.1%; p < 0.001).

Conclusions: Cellular immunity is compromised among long-term LVAD recipients because of a downregulatory cytokine imbalance and emergence of suppressive T-regulatory cells.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Mechanical circulatory support provided by the left ventricular assist device (LVAD) has been invaluable as a bridge to heart transplantation for patients with congestive heart failure. Although patient survival for the first year after LVAD placement is improved, sustained LVAD therapy is associated with an increased frequency of morbid complications [1–3]. Infection and sepsis are the leading causes for the escalated morbidity with the incidence of serious infection ranging from 20% to 60% [2–9]. These infections can be life threatening and can restrict access to heart transplantation [1, 2, 4, 10].

Because Staphylococcus organisms and fungus are the principal pathogens seen after LVAD implantation, it has been speculated that cellular immunity is impaired among LVAD recipients [2, 3, 7, 11, 12]. Temporary alterations in T-cell number or function were observed immediately after LVAD implantation, but it was unclear whether these anomalies resulted from the surgery, changes in hemodynamics, or the initial interaction between blood components and an artificial surface [7, 8, 11–14]. It has not been determined whether immune function(s) subsequently normalizes or remains abnormal with sustained LVAD exposure. We speculated that cellular immunity would remain suppressed among patients with sustained LVAD exposure, which might increase patient susceptibility to opportunistic infections. To address this speculation, we compared in vitro T-cell responses among patients treated with LVAD for a minimum of 6 months with wait-listed heart failure patients. Our results indicate that patients with sustained LVAD exposure are immunocompromised and at increased risk of lethal infection.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
This retrospective study compared diagnostic in vitro immune testing performed between 2003 and 2006 among 8 HeartMate-I and 3 Novacor recipients maintained on LVAD for a minimum of 6 months (range, 6 to 9 months) and 6 congestive heart failure patients (control patients) on the heart transplant wait-list. Patient inclusion criteria were as follows: clinically stable, living at home, and no evidence of infection within 60 days before drawing blood. Patient outcome was determined 6 months after the initial blood draw, and the occurrence of serious infections requiring medical management, death, or transplantation was recorded. The study was approved by the Institutional Review Board for the Protection of Human Subjects, which waived the need for individual consent.

Proliferative Assays
Peripheral blood mononuclear cells were enriched using Ficoll sedimentation. Viability was assessed by trypan blue exclusion and exceeded 90%. Cells were resuspended in 10% fetal bovine serum in Roswell Park Media and cultivated in microtiter plates for 4 days at 37°C in 5% CO2 in air. Cells were stimulated with 50 ng/mL anti-CD3 (Calbiochem, La Jolla, CA), 12.5 µg/mL staphylococcal enterotoxin B (SEB; Sigma, St. Louis, MO), or 5 µg/mL phytohemagglutinin P (PHA; Sigma). Tritiated thymidine was added during the last 24 hours of cultivation. Proliferation was measured by nuclear incorporation of isotope and indicated as counts per minute (cpm). Stimulation index was used to indicate the fold increase in proliferation of the stimulated cells relative to unstimulated cells as shown by the following formula:


Formula

A stimulation index greater than 10 was considered a normal proliferative response [15].

Flow Cytometric Assays
The frequency of CD3+ cells that synthesized cytokines after in vitro challenge was determined using a flow cytometric assay of intracytoplasmic cytokine expression [16]. Briefly, 6 x 106 cells in 3 mL were stimulated with SEB for 24 hours at 37°C. Four microliters of Golgi-STOP (Becton-Dickinson, San Diego, CA) was added for 4 hours at 37°C. Cells were washed and resuspended in media at 106 cells/mL. Phycoerythrin-conjugated anti-CD3 (10 µL) was added and incubated for 20 minutes at 21°C in the dark. Cells were washed and resuspended in 4% cold paraformaldehyde and incubated for 10 minutes at room temperature in the dark. Cells were washed and resuspended in 0.1% saponin (Sigma, St. Louis, MO). Cells were subsequently stained with fluorescein isothiocyanate/phycoerythrin-conjugated anti-interleukin 2 (IL-2), anti-tumor necrosis factor-{alpha} (TNF-{alpha}), anti-interferon-{gamma} (IFN-{gamma}), and anti-interleukin 10 (IL-10) for 90 minutes at 21°C in the dark. All antibodies were from R&D Systems (Minneapolis, MN). Cells were washed and resuspended in saponin buffer, then read on a BD FacScan (Becton-Dickinson). Results were gated using forward and side scatter and on the negative population using a Simultest control (Becton-Dickinson). Five thousand events were collected.

Surface phenotypes were determined. Unstimulated or SEB-stimulated cells were incubated for 20 minutes at room temperature in the dark with 10 µL of fluorescein isothiocyanate/phycoerythrin-conjugated anti-CD4, anti-CD8, anti-CD25hi, anti-CD45RO, anti-CD45RA, anti-annexin V, and anti-Fas. Because CD25 is a constituent of activated T cells, the data reflect only the percentage of CD25hi levels, which is an identifying phenotype of suppressive T-regulatory cells [17, 18]. Cells were washed, resuspended in buffer, and read on the FacScan as described above.

Statistics
Significance was determined using Student's t test, Fisher's exact test, or {chi}2 with Yates correction (Prism Software, San Diego, CA). Significance was defined as a probability value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Patients
Because of the small sample size and equivalent in vitro results (p = 0.7), results from HeartMate I and Novacor patients were combined. Patient demographics are shown in Table 1. At the time of testing, some control patients may have been slightly less sick than those if the LVAD group, but within 6 months of study closure, 2 received a heart transplant and 4 received HeartMate-I with 3 subsequently undergoing transplantation.


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  		Table 1 Patient Demographics
 
However, the frequency of morbid complications during the 6-month follow-up period was higher for LVAD than control patients. The frequency of infections requiring medical intervention or hospitalization was higher among LVAD than control patients (45.5% versus 0%; p < 0.05). Pathogens included methicillin-resistant and methicillin-sensitive Staphylococcus aureus, Pseudomonas organisms, Klebsiella organisms, Corynebacterium organisms, Burkholderia cepacia, Enterococcus organisms, and Candida glabrata. Death was more prevalent among LVAD recipients than control patients (54% versus 16%; p < 0.05). Causes of death differed between LVAD and control groups. Among LVAD recipients, death was caused by staphylococcal and fungal infections (n = 4) and stroke (n = 2), whereas the control patient (n = 1) died of cardiovascular complications. Among nonsurviving LVAD recipients (n = 6), the time from LVAD implantation to death was 8.7 ± 2.6 months (range, 7 to 11 months). Among surviving LVAD recipients (n = 5), the time from LVAD implantation to transplant was 9.2 ± 2.3 months (range, 7 to 11 months).

Proliferative Studies
Individual proliferative responses differed between LVAD patients and control patients (Fig 1). Left ventricular assist device recipients showed unusually wide variation in the range of isotopic incorporation by unstimulated cells ranging from 1,000 to 60,000 cpm. In contrast, control patients showed a typical lack of reactivity in the absence of stimulation (<1,000 cpm). Highly elevated spontaneous blastogenesis (>10,000 cpm unstimulated) was seen in 4 of 11 LVAD versus 0 of 6 control patients (p = 0.09). Retesting of the 4 LVAD patients 1 to 2 months after the initial blood draw yielded comparable results, indicating that this is a consistent feature of their immune presentation.


Figure 1
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  		Fig 1. Peripheral blood cells were stimulated with phytohemagglutinin (PHA; left), anti-CD3 (center), and staphylococcal enterotoxin B (SEB; right) as described in the text. Proliferation was measured by nuclear incorporation of isotope. Individual patient results are shown as isotopic nuclear incorporation (counts per minute [cpm]) in unstimulated (media) and stimulated cells.

 
In addition, LVAD recipients universally showed lower proliferative responses to challenge in contrast to the robust reactivity of the control group. Mean stimulation index after stimulation was lower among LVAD versus control patients for phytohemagglutinin (3.4 ± 4.7 versus 28.5 ± 19.6; p < 0.01), anti-CD3 (4.3 ± 4.5 versus 16.4 ± 17; p < 0.01), and SEB (7.2 ± 6.3 versus 26.1 ± 15.6; p = 0.002). The number of patients showing a normal stimulation index (>10) was consistently lower among LVAD versus control patients stimulated with phytohemagglutinin (1 of 11 versus 5 of 6 patients; p = 0.005), anti-CD3 (1 of 11 versus 3 of 6 patients; p = 0.05), and SEB (3 of 11 versus 5 of 6 patients; p = 0.05).

Proliferative response to in vitro challenge was examined between nonsurviving and surviving LVAD patients. Stimulation index was consistently lower among nonsurvivors than survivors for phytohemagglutinin (4.1 ± 1.4 versus 13.3 ± 5.9; p < 0.01), anti-CD3 (2.1 ± 0.6 versus 5.3 ± 2.1; p = 0.81), or SEB (3.9 ± 1.2 versus 8.4 ± 2.9; p < 0.01).

Flow Cytometric Studies
The effect of SEB challenge on cytokine upregulation in CD3+ cells is shown in Table 2. In the absence of stimulation, the percent of CD3+ cells with detectable cytoplasmic cytokines was less than 0.1% ± 0.1%. Both LVAD and control patients showed an increase in Th1 (IL-2, TNF-{alpha}, IFN-{gamma}) and Th2 (IL-10) cytokines in response to challenge (p < 0.01) relative to unstimulated cells; however, results between the groups differed qualitatively and quantitatively. After stimulation, LVAD patients showed significantly fewer CD3+ cells expressing IL-2 (p = 0.03) and TNF-{alpha} (p < 0.001) than control patients. In contrast, LVAD patients showed higher numbers of CD3+ cells upregulating IL-10 (p < 0.05) than control patients. Upregulation of CD3+IFN{gamma}+ cells was equivalent in both groups (p = 0.14).


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  		Table 2 Intracytoplasmic Expression of Cytokines in CD3+ Cells After Stimulation With Staphylococcal Enterotoxin B a
 
The frequency of cytokine upregulation was compared between nonsurviving and surviving LVAD recipients. Nonsurvivors had consistently lower frequencies than survivors for CD3+IL2+ (1.8% ± 0.2% versus 3.9% ± 1.1%; p = 0.01), CD3+TNF{alpha}+ (5.2% ± 1.4% versus 7.5% ± 2.0%; p = 0.08), CD3+IFN{gamma}+ (3.0% ± 0.7% versus 5.5% ± 2.4%; p = 0.04), and CD3+IL10+ (3.6% ± 0.8% versus 10.3% ± 5.6%; p = 0.01). Except for CD3+IFN{gamma}+, all frequencies among nonsurviving and surviving LVAD patients were lower (p < 0.01) than control patients.

To ascertain whether LVAD patients exhibited atypical frequencies of regulatory T-cell markers, surface phenotypes were compared with control patients (Table 3). CD4 and CD8 frequencies were equivalent between groups (p = 0.07). The frequency of the memory marker CD4+CD45+RO+ was equivalent (p = 0.32). However, the frequency of CD4+CD45+RA+ was highly elevated (p < 0.001) among LVAD patients, indicating that differentiated cells are more prevalent among LVAD than control patients. Testing for the suppressive T-regulatory cells (CD4+CD25hi+) showed this phenotype was more prevalent (p < 0.001) among LVAD than control patients. Lastly, the possibility that the proliferative and cytokine disparity was caused by activation-induced apoptosis among LVAD recipients was assessed by staining SEB-activated CD3+ cells with anti-annexin V and anti-Fas. However, activation-induced apoptosis was equivalent between groups. The observation that apoptotic frequencies are higher when cells are stained with Fas versus annexin V has been noted previously [14]. All phenotype frequencies were equivalent (p > 0.07) between nonsurviving and surviving LVAD recipients (data not shown).


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  		Table 3 Surface Phenotypes of Peripheral Blood Cells a
 
We compared immune variables between LVAD recipients who developed infections and those who did not (Table 4). All results were lower among those who developed infections but did not achieve significance due owing the small sample size.


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  		Table 4 Comparison of Immune Variables Between Left Ventricular Assist Device Recipients With and Without Infections a
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Infections occur early and late after LVAD implantation. Infections occurring in the early postoperative period are not unanticipated and are generally attributable to line or wound infections. In contrast, the severe infections that occur months after implantation among at-home clinically stable patients have been puzzling and led to the speculation that LVAD recipients might suffer from depressed cellular immunity [1–5]. Indeed, several studies showed temporary changes in cellular immunity immediately after LVAD placement that ranged from lymphopenia to functional anomalies among certain T-cell subpopulations [7, 8, 11, 14, 19, 20]. Because longitudinal studies were not performed, it has been unclear which, if any, immune alterations persist or whether all anomalies normalize with continued LVAD treatment. One reason to suspect that sustained LVAD exposure might cause persistent changes in immunity is the well-known biodegradation of artificial devices. Titanium devices leach metal, which has been detected in local tissue, blood cells, and plasma. It has also been shown that titanium bound to serum proteins changes the in vitro proliferative reactivity of lymphocytes [21–23]. Most recently, studies in animal models suggest that artificial devices may induce permanent changes in splenic architecture and the immune repertoire as a result of continuous leaching of metal into the periphery [24, 25]. Our study is the first to specifically evaluate cellular immunity among long-term LVAD recipients. The data indicate that long-term LVAD recipients are immunocompromised, which makes them susceptible to life-threatening opportunistic infections.

Despite the small study size, clinical outcome among our LVAD patients was consistent with larger studies performed in the same time epoch showing approximately half the patients succumbed to lethal infections within the first year after LVAD placement [1–6, 9, 10]. Cellular immunity was assessed using three in vitro indicators: proliferative response to challenge, Th1/Th2 cytokine elaboration, and frequency of regulatory phenotypes. By all indicators, LVAD recipients showed an atypical and suboptimal immune response. In contrast, the in vitro immune performance of control patients was robust and equivalent to our previous findings with healthy volunteers [15, 23].

T-cell proliferative responses were evaluated using stimuli triggering different activation pathways including the T-cell receptor (anti-CD3), superantigen (SEB), and membrane crosslinking (phytohemagglutinin). All LVAD patients showed abnormal and suboptimal reactivity that was not seen in control patients. Nearly 40% of LVAD patients showed high levels of autoreactivity as shown by T cells that were nonspecifically dividing and unable to respond appropriately to an antigen-specific challenge. This phenomenon has been observed immediately after LVAD placement and may reflect an inappropriate and persistent response to the device or continuous ion leaching from the device [8, 12, 14, 21–23]. The remaining LVAD recipients showed proliferative hyporesponsiveness. This sustained insufficient response was not caused by activation-induced apoptosis or depletion of CD4 or T-memory cell populations. This observation differs from studies performed in the immediate postimplantation period that showed leukopenia and elevated levels of activation-induced apoptosis [7, 8, 19].

It appears that maintenance of the insufficient proliferative response among long-term LVAD recipients may be driven by a prevalence of downregulatory elements. Although it has been speculated that LVAD patients might overexpress suppressive Th2 cytokines, the data have been inconclusive [12, 13]. Our study showed that although LVAD recipients can synthesize both proinflammatory and antiinflammatory cytokines, the balance is skewed toward a suppressive Th2 phenotype. In contrast, heart failure control patients displayed a normal proinflammatory Th1 phenotype. Studies among patients with immunomodulatory diseases have shown that this type of cytokine imbalance can inhibit appropriate proliferative response to antigenic challenge and increase patient susceptibility to infections [15, 26]. In addition, elevated suppressive T-regulatory cells among LVAD patients may contribute to the sustained inadequate proliferative reactivity. CD4+CD25hi+ cells are critical downregulatory agents of cellular immunity and have been shown to suppress T-cell activation and Th1 cytokine elaboration in autoimmune disease and hepatocellular carcinoma [19, 20, 24]. Our study found that all the long-term LVAD recipients had high levels of suppressive T-regulatory cells. In contrast, control patients demonstrated a normal phenotype [17, 18, 27]. The suppressive combination of cytokine imbalance and elevated suppressive T-regulatory cells probably contributes to the proliferative hyporeactivity among LVAD recipients and the persistence of clinical immunoinsufficiency.

The immune responses of the nonsurviving LVAD patients were consistently lower than those of the surviving patients. Although interesting, this observation has little predictive utility because both groups showed profound immunoinsufficiency and the differences between nonsurviving and surviving patients were small. We also observed that immune variables were lower among LVAD patients who developed infections than those who did not. Whether any variable(s) would be useful as a predictive marker for increased susceptibility to infection cannot be determined with this small sample size, but this issue underscores the need for longitudinal assessment after device implantation.

This study showed that cellular immunity is compromised among all long-term LVAD recipients and increases susceptibility to life-threatening infections. Whether the different biomaterials of the HeartMate II will produce similar immune effects will need to be determined. Given our current level of understanding, we recommend that antioxidant therapy to scavenge metallic ions as well as prophylactic antibiotic or antifungal therapy may benefit patients receiving long-term exposure to LVAD. These considerations are of critical importance because of the increasing use of LVADs as well as the increasing use of artificial devices to treat human disease.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Martin J, Friesewinkel O, Benk C, Sorg S, Schultz S, Beyersdorf F. Improved durability of the HeartMate XVE left ventricular assist device provides safe mechanical support up to 1 year but is associated with high risk of device failure in the second year J Heart Lung Transplant 2006;25:384-390.[Medline]
  2. Holman WL, Park SJ, Long JW, et al. Infection in permanent circulatory support: experience from the REMATCH trial J Heart Lung Transplant 2004;23:1359-1365.[Medline]
  3. Kalya AV, Tector AJ, Crouch JD, et al. Comparison of Novacor and HeartMate vented electric left ventricular assist devices in a single institution J Heart Lung Transplant 2005;24:1973-1975.[Medline]
  4. Chinn R, Dembitsky W, Eaton L, et al. Multicenter experience: prevention and management of left ventricular assist device infections ASAIO J 2005;51:461-470.[Medline]
  5. Bentz B, Hupcey J, Polomano R, Boehmer J. A retrospective study of left ventricular assist device-related infections J Cardiovasc Manag 2004;15:9-16.[Medline]
  6. Kasirajan V, McCarthy PM, Hoercher KJ, et al. Clinical experience with long-term use of implantable left ventricular assist devices: indications, implantation, and outcome Semin Thorac Cardiovasc Surg 2000;12:229-237.[Medline]
  7. Ankersmit HJ, Edwards NM, Schuster M, et al. Quantitative changes in T cell populations after left ventricular assist device implantation Circulation 1999;100(Suppl):II-211-II-215.[Medline]
  8. Rothenburger M, Wilhelm M, Hammel D, et al. Immune response in the early postoperative period after implantation of a left ventricular assist device system Transpl Proc 2001;33:1955-1957.[Medline]
  9. Malani PN, Dyke DB, Pagani FD, Chenoweth CE. Nosocomial infections in left ventricular assist device recipients Clin Infect Dis 2002;34:1295-1300.[Medline]
  10. Simon D, Fischer S, Grossman A, et al. Left ventricular assist device-related infection: treatment and outcome Clin Infect Dis 2005;40:1108-1115.[Medline]
  11. Deng MC, Erren M, Tjan TD, et al. Left ventricular assist system support is associated with persistent inflammation and temporary immunosuppression Thorac Cardiovasc Surg 1999;47:326-331.[Medline]
  12. Itescu S, Andersmit JH, Kocher AA, Schuster, MD. Immunobiology of left ventricular assist devices Prog Cardiovasc Dis 2000;43:67-80.[Medline]
  13. Clark AL, Loebe M, Potapov EV, et al. Ventricular assist device in severe heart failure: effects on cytokines, complement and body weight Eur Heart J 2001;22:2275-2283.[Abstract/Free Full Text]
  14. Itescu S, John R. Interactions between the recipient immune system and the left ventricular assist device surface: immunological and clinical implications Ann Thorac Surg 2003;75(Suppl):S58-S65.[Abstract/Free Full Text]
  15. Kimball PM, Shiffman M, Verbeke S. Proliferative suppression and class I insufficiency on peripheral blood cells from hepatitis C patients overcome by exogenous cytokines or high dose mitogen Clin Immunol 2002;103:317-323.[Medline]
  16. Woitas RP, Lechmann M, Jung G, Kaiser R, Sauerbruch T, Spengler U. CD30 induction and cytokine profiles in hepatitis C virus core-specific peripheral blood T lymphocytes J Immunol 1997;159:1012-1018.[Abstract]
  17. Trzonkowski P, Szmit E, Mysliwska J, Mysliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence Clin Immunol 2006;119:307-316.[Medline]
  18. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25+hi regulatory cells in human peripheral blood J Immunol 2001;167:1245-1253.[Abstract/Free Full Text]
  19. Ankersmit H, Tugudea S, Spanier T, et al. Activation induced T cell death and immune dysfunction after implantation of left ventricular assist device Lancet 1999;354:550-555.[Medline]
  20. Schuster M, Kocher A, John R, et al. B cell activation and allosensitization after left ventricular assist device implantation is due to T cell activation and CD40 ligand expression Hum Immunol 2002;63:211-220.[Medline]
  21. Zaffe D, Bertoldi C, Consolo U. Element release from titanium devices used in oral and maxillofacial surgery Biomaterials 2003;24:1093-1099.[Medline]
  22. Frisk P, Lindvall A, Hudecek R, Lindh U. Decrease of trace elements in erythrocytes and plasma after removal of dental amalgam and other metal alloys Biol Trace Elem Res 2006;113:247-259.[Medline]
  23. Hallab NJ, Midecz K, Vermes C, Skipor A, Jacobs JJ. Orthopaedic implant related metal toxicity in terms of human lymphocyte reactivity to metal-protein complexes produced from cobalt-base and titanium-base implant alloy degradation Mol Cell Biochem 2001;222:127-136.[Medline]
  24. Busuttil SJ, Drumm C, Plow EF. In vivo comparison of the inflammatory response induced by different vascular biomaterials Vascular 2005;13:230-235.[Medline]
  25. Ferreira ME, de Lourdes Pereira M, Garcia e Costa F, Sousa JP, de Carvalho GS. Comparative study of metallic biomaterials toxicity: a histochemical and immunohistochemical demonstration in mouse spleen J Trace Elem Med Biol 2003;17:45-49.[Medline]
  26. Kimball PM, Elswick R, Shiffman M. Ethnicity and cytokine production gauge response of patients with hepatitis C to interferon-a therapy J Med Virol 2001;65:510-516.[Medline]
  27. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma Cancer Res 2005;65:2457-2464.[Abstract/Free Full Text]

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