International Immunopharmacology 18 (2014) 169–174

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Effects of opioid therapy on human natural killer cells Giovanna Tabellini a, Elisa Borsani b,⁎, Marzia Benassi a, Ornella Patrizi a, Doris Ricotta c, Luigi Caimi c, Roberto Lanzi b, Fabrizio Micheli d, Vittorio Iorno e, Raffaella Bettaglio f, Rita Rezzani b, Luigi F. Rodella b, Silvia Parolini a a

Department of Molecular and Translational Medicine, Division of Experimental Oncology and Immunology, University of Brescia, Brescia, Italy Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Brescia, Italy Department of Molecular and Translational Medicine, Division of Biotechnology, University of Brescia, Brescia, Italy d Pain Therapy Center, Guglielmo da Saliceto Hospital, Piacenza, Italy e Pain Medicine Center “Mario Tiengo”, IRCCS Foundation, Major Hospital Policlinico Mangiagalli and Regina Elena, Milan, Italy f Unit of Palliative Care and Pain Therapy, “S. Maugeri” Foundation, IRCCS, Pavia, Italy b c

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Article history: Received 2 July 2013 Received in revised form 4 November 2013 Accepted 12 November 2013 Available online 25 November 2013 Keywords: Human subjects Chronic pain Opioid therapy NK cells

a b s t r a c t Opioid compounds, such as morphine, induce powerful analgesic effects and are extensively used clinically to treat a wide variety of pain. The aim of our study was to evaluate the impact of opioid therapy on phenotype and function peripheral blood NK cells. The patients were referred to three Italian pain therapy centers (Milan, Pavia, Piacenza) for chronic pain in neuropathic or mixed somatic components. The patients were between 18 and 75 years old and were of Caucasian ethnicity. We studied the expression of activating and inhibitory NK receptors to discriminate NK subsets with different CD56 surface expression intensities (CD56bright and CD56dull NK cells). The flow cytometry analysis of the NK cells was at normal levels in peripheral blood lymphocytes with fewer CD56bright compared to the CD56dull NK cell subset when compared to blood from drug free donors. Furthermore, the cytolytic activity of in vitro patient NK cells analyzed was not lower, as would be expected from the regular expression of activating NK receptors for both subsets. Taken together, these data indicate that NK cells from opioid treated patients do not show any signs of NK cell immune-suppression. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Opioid compounds are extensively used in a clinical setting to treat various types of pain. Opioid agonists are a group of natural, semisynthetic, or synthetic compounds acting on a series of receptors, such as mu, kappa and delta receptors. In addition to their therapeutic value, opioids also produce a number of undesirable effects such as respiratory depression, constipation and physical dependence. Opioid agonists have also been shown to disrupt the immune response. Indeed, there is an abundance of data demonstrating that the administration of morphine alters immune status including suppression of natural killer cell (NK) activity [1,2], mitogen induced T- and B-lymphocyte proliferation [2,3], antibody formation [4] and cytokine production [5]. Consistent with these observations, opioid administration has been associated with the increased susceptibility of certain animals to bacterial and viral infections [6] as well as and with decreased survival in cancerbearing animals [7]. While a lot of attention has been focused on morphine's ability to alter numerous immunity indices, the generality of these immune-modulatory ⁎ Corresponding author at: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. Tel.: +39 0303717479; fax: +39 0303717486. E-mail address: [email protected] (E. Borsani). 1567-5769/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.intimp.2013.11.015

effects on other opioid compounds which also function through the mu opioid receptor remains unclear. Therefore, it is still uncertain how partial or low efficacy mu opioid agonists, which produce various degrees of mu opioid receptor stimulation, can modulate the immune system. As a result, we analyzed NK cell populations derived from opioid treated patient peripheral blood samples comparing them with drug free donor samples. NK cells are the third subset of lymphocytes and are important for the early immune response to viral and microbial infections and tumor cells [8,9]. They are large granular lymphocytes that express the surface markers CD56 (adhesion molecule mediating homotypic adhesion) and CD16 (FcγRIIIA, low-affinity receptor for the Fc portion of immunoglobulin G) in humans. The NK cell population is regulated by a balance of activating and inhibitory signals from cell surface receptors [10]. The inhibitory signals are mediated mainly by HLA class-I binding receptors, including killer cells Ig-like receptors (KIRs) and CD94/ NKG2A [11]. Activating signals are encoded by a wide array of receptors, including NKp46, NKp30, NKp44 (named Natural Cytotoxicity Receptors, NCRs), NKG2D and various activating NCR co-receptors. In human peripheral blood, two NK cell subsets can be defined on the basis of the relative expression of the markers CD56 and CD16 [12–14]. The CD56dull CD16+ NK cells constitute at least 90% of all peripheral blood NK cells and are therefore the major circulating subset responsible for antibody-dependent cellular cytotoxicity mechanism.

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Table 1 Details on patients and drug free subjects (F = female; M = male). No. patient

Sex

Age (years)

Therapy

Dose

Type of pain

1 2 3 4 5 6 7 8 9 10 11 12 13 14

F F F F F F M F F F F M F F

61 57 48 66 61 60 72 64 72 51 71 56 50 68

Subarachnoid morphine Subarachnoid morphine Intrathecal morphine Intrathecal morphine Transdermal buprenorphine Subarachnoid morphine Subarachnoid morphine Subarachnoid morphine Transdermal buprenorphine Per os oxycodone Per os methadone Per os methadone Intrathecal morphine Per os oxycodone

2.2 mg/die 1 mg/die 1 mg/die 1.4 mg/die 70 μg/h 1 mg/die 5 mg/die 1.4 mg/die 17.5 mg/die 60 mg/die 6 mg/die 7 mg/die 1.5 mg/die 40 mg/die

Mixed Mixed Mixed Mixed Mixed Mixed Mixed Mixed Mixed Mixed Neuropathic Mixed Mixed Neuropathic

No. drug free subject

Sex

Age (years)

Therapy

Dose

Type of pain

1 2 3 4 5 6 7 8 9

F F F F F M M F F

61 59 42 51 58 34 50 43 48

None None None None None None None None None

None None None None None None None None None

Mixed Neuropathic None None None None None None None

The remaining 10% at most, of NK cells, i.e. CD56bright CD16−, produce immune-regulatory cytokines and are the major interferon-producers [12,14]. The cell function of NK cells depends on the expression of activation markers that include growth factor receptors such as CD25 (a component of the receptor for IL-2), and molecules whose cellular function is not fully understood, such as CD69. Upon stimulation with cytokines such as IL-2 or IL-12, the cytotoxic activity of all NK cell subset greatly increases. The aim of our work was to analyze the relationship between the opioid administration of suffering patients and the immune NK cell response. 2. Materials and methods

subarachnoid delivery. Patients receiving opiates for less than 6 months were also excluded.

2.2. PBMC purification Peripheral blood mononuclear cells (PBMCs) were obtained from heparinized blood by density gradient centrifugation over Ficoll (Sigma, St. Louis, MO). PBMCs were re-suspended in RPMI 1640 medium, supplemented with 2 mM glutamine, 50 g/ml penicillin, 50 g/ml streptomycin and 10% heat-inactivated FCS (PAA Laboratories GmbH, Linz, Austria).

2.1. Recruitment and selection of patients The multi-center study was approved by the Ethical Committee of Guglielmo da Saliceto Hospital of Piacenza and written informed consent was obtained from all patients. The research included patients referred to three pain therapy centers in Italy (Milan, Pavia and Piacenza) under medical monitoring for chronic pain in somatic components, both neuropathic or mixed. Enrollment involved patients between 18 and 75 years old and of Caucasian ethnicity. Those patients whose therapy included other drugs influencing the immune system were not included. An exception was made for patients treated with steroids, who were considered after a suspension period of 40 days, as well as patients treated with tramadol after a suspension period of 1 week. Furthermore, chronic diseases which affected the immune system in any way (autoimmune diseases, etc.) were also excluded. We collected 20 ml of peripheral vein blood from each patient in a sterile test tube containing 5000 IU/ml of heparin as an anti-coagulant. We identified two groups (Table 1): 1. drug free subjects (n.9 control subjects — median age of 50 years old) including patients without pain or under medical monitoring for chronic pain within somatic components, neuropathic or mixed without a concurrent pain therapy. 2. patients (n.14 — median age of 61 years old) treated chronically with opioids per os, transdermal delivery, intrathecal delivery or

2.3. Monoclonal antibodies and flow cytofluorimetric analysis The following mAbs, produced in our lab and kindly provided by A. Moretta (DIMES, University of Genoa), were used in this study: BAB281 (IgG1 anti-NKp46), AZ20 (IgG1 anti-NKp30), AZ140 (IgG1 anti-NKp44), ON72 or BAT221 (IgG1 anti-NKG2D), SUS142 or KD1 (IgG2b and IgG2a anti-CD16), FS280 or C218 (IgG2a and IgG1 antiCD56), C227 (IgG1 anti-CD69), GL183 (IgG1 anti-KIR2DL2/L3/S2), 289 (IgG2a anti-CD3), HP2.6 (IgG2a anti-CD4), B9.4 (IgG2b anti-CD8), XA 185 (IgG1 anti-CD94), Z270 (IgG1 anti-NKG2A), D1-12 (IgG2a antiHLA-DR), AZ115 (IgG1 anti-p50.1 e p58.1), AZ158 (IgG2a antiKIR3DL1/S1/L2), and MAR 93 (IgG1 anti-IL-2R). For one- or two-color cytofluorimetric analysis, cells were stained with the appropriate mAbs followed by PE- or FITC-conjugated isotype-specific goat antimouse secondary antibody (Southern Biotechnology, Birmingham, AL). Cell acquisition was performed on a FACSCalibur flow cytometer (Becton Dickinson, Mountain View, CA) and data analyzed using the CellQuest software (Becton Dickinson).

2.4. Cytolytic activity PBMCs from patients and healthy donors (exposed or not to rIL-2) were tested for cytolytic activity against NK-susceptible tumor target cells K562 in a 4-hour 51Cr-release assay as previously described [15]. The effector–target (E/T) ratios are indicated in the figure legends.

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Comparisons among samples were analyzed for statistical significance by the Student's t-test using the Microsoft Excel software. p value b 0.05 was considered as significant.

and concentration so we had to consider all patients belonging to a single heterogeneous group. The aim of this work was to study and compare phenotype and cytolytic activity of NK cells derived from treated patients belonging to three Italian centers of pain therapy with those from control subjects.

3. Results

3.1. Phenotypic characterization of NK cells

We evaluated the impact of opioid therapy on NK cells in patients suffering from chronic pain in somatic, neuropathic or mixed component (Table 1). The patients were heterogeneous in therapeutic opioid approach, even if most of them were treated with morphine. The pain threshold, even for the same pathology, could be very different however among these patients. A specific treatment was therefore needed that considered the individual perception of pain. This important clinical aspect did not allow us to strictly select patients for the same drug

Here, we analyzed the expression of different NK receptors by flow cytometry. It is interesting to note that NK cells play a crucial role against tumor and virus infected cells due to the fine balance between activating and inhibitory receptors. Our analysis of NK cell receptors has allowed us to better discriminate NK subsets which are characterized by different surface intensities of CD56 expression. In particular NK cells CD56dull are CD16+ and co-express various KIR molecules and/or NKG2A, while NK cells CD56bright CD16− only express

2.5. Statistical analysis

Fig. 1. Flow cytometry phenotypic analysis of NK cells. Freshly isolated peripheral blood lymphocyte cells (PBLs) from drug free donor (CTR) and from opioid patients (PT) were analyzed by flow cytometry in two-color immunofluorescence for the expression of CD56 with CD16, NKp46, CD69 and NKG2A respectively. The dot plots of representative drug free subjects and patients are shown. The rectangle indicates the single and double positive CD56bright cells.

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Fig. 2. Expression of surface molecules on NK cell population CD56+CD3− gated on peripheral blood lymphocytes. The white column shows the average value with standard deviation of nine drug free subjects (CTRs). The gray columns, numbered from one to fourteen (1→14), show the percentage values of each patient (PT).

the inhibitory molecule NKG2A. Both NK cell subsets express the activating NK receptors NCR (i.e. NKp46, NKp30), NKG2D and various co-receptors. Moreover different expression profiles of chemokine receptors from the two major blood NK cell subsets are also responsible for the preferential migration of CD56dull CD16+ and CD56bright CD16− NK cells to inflamed tissues and secondary lymphoid organs respectively. We therefore analyzed (using double fluorescence) the different surface molecules expressed on CD56+CD3− NK cells. The whole NK cell receptor repertoire including activating molecules CD16, NCRs (NKp46, NKp30 and NKp44), and NKG2D, inhibitory molecules KIRs and NKG2A and activation markers (CD69 and CD25) was analyzed on NK cells derived from patients' peripheral blood. In Fig. 1 we show the representative dot plots of some NK cell markers (CD16, NKp46, CD69, NKG2A) derived from patient peripheral blood compared with the representative dot plots of drug free subject. In Fig. 2(A, B, C and D) we have shown the expression histograms of the same markers with percentage values for each patient. In each histogram, the first column indicates the average of control values with the standard deviation. We have also shown the patient percentage values of CD56+CD3− derived from peripheral blood lymphocytes (Fig. 2E). Peripheral blood CD56+CD3− NK cell percentage did not significantly differ between patients and controls. Regarding the expression of NK cell receptors, we did not see any altered expressions of CD16, NCRs (NKp46, NKp30 and NKp44) and NKG2A in NK cells from patients compared to controls. Usually, in healthy subjects, NCRs (NKp46 and NKp30) are expressed on the whole NK cell population with only a slight variation of the expression intensity among subjects. Furthermore, CD16 is strictly associated with the more mature NK cell CD56dull subset (90–95%) and NKG2A, always expressed on NK cell CD56bright subset (5–10%), is variably co-expressed with KIR molecules on NK cell CD56dull in a range between 30 and 60%. We observed a reduction of the CD56bright subset when NK cells were immune-stained with CD16, NKG2A (Fig. 1) and CCR7 (data not

shown) in most patients. Indeed, we noted an expansion of the CD56dull CD16+ NK cell subset characterized by the surface expression of all different KIR molecules. We also found a lower NKG2A expression on CD56 NK cells derived from patients also due to increased surface expression of KIR molecules on the CD56dull NK cell subset. Interestingly, we detected high expressions of the activation marker CD69 (early activation antigen of NK and T cells) on CD56+ cells with a range between 6% and 20% on CD56dull compared to drug free subjects (1–6%) (Figs. 1 and 2). We also observed increased expression of IL2R/ CD25 on NK cell samples from patients (data not shown). Fig. 1 also shows the cell population CD56− CD69+ belonging to T lymphocyte cells.

3.2. NK cell function We previously explained that the control group was composed of healthy donors without pain or patients with pain treated without opioids. This control group showed a homogeneous phenotype of the NK cell activating receptor expression as observed on NK cells derived from the patient group. In order to define the functional capability of NK cells, freshly isolated peripheral blood mononuclear cells (PBMCs) from all patients were analyzed for cytolytic activity against the NK cell susceptible human erythroleukemia cell line K562, before and after overnight rIL-2 culture. The cytolytic activity of NK cells derived from patients was not reduced compared to that of control NK cells. Indeed, IL2 activated NK cell cytotoxicity and non-activated NK cell cytotoxicity were in some cases higher than control donor NK cell cytolysis. We show in Fig. 3 different ratio cytotoxic values from activated and non-activated IL2 NK cells from both groups. Furthermore, we did not see any differences of NK cell cytotoxic capability of patient groups from the three centers as can be seen in Table 1. Statistical analyses showed that average values of IL2 activated NK cells from treated patients were significantly higher than controls especially at higher ratios (p b 0.05).

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Fig. 3. Functional analysis of NK cells. Freshly isolated peripheral blood mononuclear cells derived from control subjects (□) and from patients (●) were tested against the K562 target cells line either without (A) or with (B) overnight incubation in the presence of rIL-2 at different E/T ratios. Data from the control group (9) and patients (14) show the mean+/−SD of 3 replicates (p b 0.05, Student's t-test) in the upper panel. Lower panel shows the data of each control subject (□) and patient (●).

Taken together, our data indicate that NK cells from patients are no less capable of mediating cytolytic activity which generally is in accordance with the other authors. We believe that these results could be related to the surface expression of activation antigens CD69 and IL2R and of the normal levels of triggering receptors. 4. Discussion and conclusions Several animal study authors have shown that opioid agonist therapy might interfere with the immune response. In this study, we analyzed the effects of drug treatment on NK cells from a statistically significant group of patients undergoing analgesic therapy from three centers of pain therapy in Italy. In particular, we analyzed the NK cells from patient peripheral blood by studying the expression of different activating and inhibitory receptors and their functional cytolytic activity. The opioid agonists used in our study were as follows: buprenorphine, morphine, methadone and oxycodone. Buprenorphine is a mu opioid agonist of intermediate efficacy that is used clinically for pain management and has recently been approved for treatment of opioid dependence. Various studies have sustained that opioid drugs (morphine, methadone, oxycodone) have a particular immune-suppressive profile on immunological response [16–18]. Indeed, morphine (MF) and other opioids have been commonly thought to down-regulate the immune responsiveness [19]. The existence of opioid receptors on immune cells [20,21] can explain specific and direct opioid mediated immune-regulation. MF has been reported to suppress mitogen-induced lymphocyte proliferative responses [22,23], macrophage activation [3], macrophage mediated inhibition of tumor cell proliferation [24], phagocytosis [24,25], antibody formation [25], production of interferon-γ [16,23,26] and the number of circulating lymphocytes [27]. Interestingly, some authors argue that MF also suppresses NK cell activity [24,26,28,29]. Because it has been shown that the immune-suppressive effects of morphine are evident at larger doses than those needed for controlling pain, larger doses than 10 mg of morphine may be needed to observe the suppression of NK activity in humans [17]. This would agree with our data since the administered morphine doses to patients did not exceed 10 mg/die. Indeed, we did not observe any particular effect on NK cell activity in the opioid patients or due to the different

concentrations and administration routes (subarachnoid, intrathecal, oral and trans-dermal). In this connection, Borman and co-workers [19] observed that low doses of MF (0.5 mg/kg) in pigs could markedly increase cytotoxicity without any corresponding changes in circulating large granular lymphocyte (LGL) number. On the contrary, in pig cases of 1.0 and 5.0 mg/kg, this increase was smaller and was followed by less activity and number of LGL cells. Most research has looked at immune response effects of opioids in rodents in which the use of buprenorphine and MF did not produce any significant changes of splenic natural killer cell function, T-cell proliferation or macrophage functions, whereas tramadol use could increase NK cell activity. These findings would confirm our own results [30,31]. In our experience, patients did not show any changes in NK cell number in the peripheral blood (data not shown) and flow cytometry analysis did not reveal any abnormal expression of NK receptors. In particular, activating NK receptor expression, NCRs and NKG2D, involved in tumor cell recognition, was comparable to the control group NK cells. As a result, patient NK cell activity was not suppressed and we did not observe any opioid agonists and/or dose dependent effects. In some cases, patient NK cytotoxicity was slightly higher but still statistically significant, than control NK cell activity. Various authors [32,33] have reported that anesthesia, surgical stress, pain and drugs used for analgesia do affect immune status, including NK cell activity. In our study, we were not able to control and verify possible patient stress or pain levels (as noted). However we did see that our entire heterogeneous group of patients had activation marker expression (CD69 and CD25) on the NK cell CD56dull subset derived from peripheral blood. We could speculate that NK cell activation in the peripheral blood could justify the slight increase of certain patients' NK cell cytotoxicity or the normal NK cell activity observed compared to normal control NK cells. In humans, some studies on the effects of these drugs on immune responses have shown an increase of NK activity of circulating lymphocytes [34,35]. These authors consider that this effect could be due to the increase traffic of lymphocytes CD56+CD16+ in the peripheral blood [35]. However, they did not analyze the different NK cell subsets of peripheral blood from patients although their results do agree with our finding of increased cytotoxic CD56dull CD16+ NK cell subset in our patients. Indeed, two distinct NK cell subsets have recently been

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characterized from the cell surface intensity of CD56 molecule and expression of CD16: i.e. the CD56dull CD16+ NK cell subset which makes up approximately 90% of circulating NK cells and the CD56bright CD16− NK cell subset that accounts for the other 10%. So, CD56dull NK cells are an important effector immune cell population not only for their ability to kill abnormal cells, but also for their ability to induce rapid inflammatory responses by recruiting of other defensive cells and promoting cellular resistance to infection together with initial adaptive immune responses. In our patients, we showed an important reduction of the CD56bright subset by flow cytometry. These are immature NK cells that produce immune-regulatory cytokines, including IFN-γ, TNF-α and GM–CSF as well as expansion of more cytotoxic CD56dull KIR+ NK cell subset. This may be due to NK cell stimulation observed in our patients. We can therefore suppose that opioid treatment does not prevent the functional cytolytic ability of NK cells during the pathological and inflammatory status of patients. Interestingly, we observed the expression of activation molecules as CD69 and CD25 on patient NK cells. It is not easy to establish whether the expression of activation markers in patients' resting NK cells was due to their pathological conditions or the consequences of pharmacological opioid drug treatment. Currently the underlying mechanism of opioid-induced changes to human NK cells in vivo has not been investigated enough. Therefore, further experiments are necessary to clarify the real consequences of opioid treatment on cell innate immunity responses. Acknowledgment SP, GT, OP, and MB are supported by Ministero dell'Istruzione dell'Università e della Ricerca (PRIN 2008 PTB3HC_002) and DR by Centro di Studio e Ricerca “Quality and Technology Assessment, Governance and Communication Strategies in Health Systems”. We thank Professor Alessandro Moretta for providing the monoclonal antibodies anti-NK cell receptors, produced in his laboratory at Dipartimento di Medicina Sperimentale, Università di Genova, Italy. We thank Dr. Robert Coates for his editorial assistance. References [1] Shavit Y, Depaulis A, Martin FC, Terman GW, Pechnick RN, Zane CJ, et al. Involvement of brain opiate receptors in the immune-suppressive effect of morphine. Proc Natl Acad Sci U S A 1986;83:7114–7. [2] Bayer BM, Daussin S, Hernandez M, Irvin L. Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. Neuropharmacology 1990;29:369–74. [3] Bryant HU, Bernton EW, Holaday JW. Immunomodulatory effects of chronic morphine treatment: pharmacologic and mechanistic studies. NIDA Res Monogr 1990;96:131–49. [4] Lockwood LL, Silbert LH, Fleshner M, Laudenslager ML, Watkins LR, Maier SF. Morphine-induced decreases in in vivo antibody responses. Brain Behav Immun 1994;8:24–36. [5] Hung CY, Lefkowitz SS, Geber WF. Interferon inhibition by narcotic analgesics. Proc Soc Exp Biol Med 1973;142:106–11. [6] Risdahl JM, Khanna KV, Peterson PK, Molitor TW. Opiates and infection. J Neuroimmunol 1998;83:4–18. [7] Yeager MP, Colacchio TA. Effect of morphine on growth of metastatic colon cancer in vivo. Arch Surg 1991;126:454–6. [8] Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999;17:189–220.

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Effects of opioid therapy on human natural killer cells.

Opioid compounds, such as morphine, induce powerful analgesic effects and are extensively used clinically to treat a wide variety of pain. The aim of ...
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