The effect of trauma-focused therapy on the altered T cell distribution in individuals with PTSD: Evidence from a randomized controlled trial

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Abstract

Posttraumatic stress disorder (PTSD) is associated with a reduced ratio of naïve cytotoxic T lymphocytes, an increased ratio of memory cytotoxic T lymphocytes, and a reduced proportion of FoxP3+ regulatory T lymphocytes. This study investigated whether these immunological alterations are reversible through an evidence-based psychotherapeutic treatment. Therefore, 34 individuals with PTSD were randomly assigned to either a treatment condition of 12 sessions narrative exposure therapy (NET) or a waitlist control (WLC) group. PTSD symptoms were significantly reduced in the NET group, but not in the WLC group, four months post-therapy (effect size: Hedges' g = −1.61). One year after therapy, PTSD symptoms were improved even further in the NET group compared to baseline (Hedges' g = −1.96). This symptom improvement was mirrored in an increase in the originally reduced proportion of regulatory T cells (Tregs) in the NET group at the one-year follow-up, when comparing subgroups matched for baseline Treg numbers. However, no changes were found for the initially reduced proportion of CD45RA+CCR7+ naïve T lymphocytes. In conclusion, NET was effective in reducing trauma-related PTSD symptoms and had a positive effect on the proportion of Tregs cells, thus demonstrating an effect of psychotherapy on an immunological level. Yet, the shift in the proportion of naïve and memory T lymphocytes in individuals with PTSD, discussed in the literature as a correlate of premature immunosenescence, was not reversible and thus might render these patients permanently more susceptible to infectious diseases.

Introduction

The probability of developing posttraumatic stress disorder (PTSD) after psychological trauma increases with the number of traumatic event types experienced (Neuner et al., 2004a, Kolassa et al., 2010). Likewise, a dose–response effect of trauma exposure during childhood has been demonstrated for the development of physical health problems (Felitti et al., 1998) and impaired brain development (Teicher et al., 2012). Furthermore, an increased risk for somatic diseases like chronic pain, cancer, cardiovascular, respiratory, gastrointestinal, and autoimmune diseases has been reported for individuals with PTSD (Boscarino, 2004, Boscarino et al., 2010, Sareen et al., 2007), where the poor physical health found in individuals with PTSD might be moderated by altered immune functions and inflammatory processes (Von Känel et al., 2007, Pace and Heim, 2011, Spitzer et al., 2010).

However, linking PTSD to alterations of bulk T cell populations, representing a major branch of adaptive immunity, has been controversial: Whereas the number of circulating CD8+ cytotoxic T cells in individuals with PTSD has been found to be mostly lower (Ironson et al., 1997, Kawamura et al., 2001, Sommershof et al., 2009) or unchanged (Altemus et al., 2006, Laudenslager et al., 1998, Vidović et al., 2007, Wilson et al., 1999), the number of circulating CD3+ T lymphocytes or CD4+ T helper cells has been found to be lower, unchanged or even higher (Ironson et al., 1997, Laudenslager et al., 1998, Boscarino and Chang, 1999, Wilson et al., 1999, Kawamura et al., 2001, Boscarino, 2004, Vidović et al., 2007, Sommershof et al., 2009). As peripheral T lymphocytes consist of a range of functionally different subpopulations, one reason for these inconsistent findings might be that changes in PTSD might be specific to certain T lymphocyte activation and differentiation states. Sommershof et al. (2009) investigated this further differentiation of CD4+ T helper and CD8+ cytotoxic T cells in naïve, memory and effector cells, applying a differentiation model of T cells defined by changes in the expression of the lineage markers CD45RA and CCR7 (Hamann et al., 1999, Sallusto et al., 1999). They found a decreased ratio of (CD45RA+CCR7+) naïve CD8+ T cells and an increased proportion of (CD45RA) memory CD8+ T cells in individuals with PTSD (Sommershof et al., 2009). As a shrinking repertoire of naïve T cells may correlate with an enhanced susceptibility to infectious diseases (Fagnoni et al., 2000, Shen et al., 1999), this reduction in naïve T cells represents a possible explanation for the enhanced risk of infectious diseases in individuals with PTSD (Sommershof et al., 2009). Furthermore, Sommershof et al. (2009) observed a 50% decrease in the proportion of CD4+CD25+FoxP3+ regulatory T cells (Treg) in individuals with PTSD. Treg cells are critical for maintaining balance in the immune system, regulating the immune response, and preventing autoimmune diseases (Vignali et al., 2008). Decreased counts of CD4+CD25+FOXP3+ Treg cells have been associated with autoimmune diseases like diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis, anemia and eczema (Bennett et al., 2001, Buckner, 2010, Wildin et al., 2002), conditions for which individuals with PTSD show an increased risk (Boscarino, 2004, Boscarino et al., 2010, Weisberg et al., 2002).

Given the considerable prevalence of traumatic stress, and in particular the high prevalence of PTSD in populations affected by conflict, terror and combat (Neuner et al., 2004a, Neuner and Elbert, 2007), a highly relevant question in the context of traumatic stress and physical disease is: Can effective treatment reverse the effects of traumatic stress not only on a psychological but also on an immunological level?

Trauma-focused psychotherapeutic interventions may effectively reduce trauma-related mental suffering in individuals with PTSD (Ehlers et al., 2010, Cloitre, 2009, Kleim et al., 2012, Seidler and Wagner, 2006), and, in individuals with PTSD with comorbid borderline personality disorder (Bohus et al., 2013) or comorbid substance abuse (van Dam et al., 2013). Moreover, it was demonstrated that successful psychotherapeutic treatment also significantly reduced cough, diarrhea, and fever (Neuner et al., 2008).

Yet, to our knowledge no study investigated the effect of psychotherapy on T lymphocyte distribution in individuals with PTSD. So far, the impact of psychological interventions on T lymphocyte populations has mainly been examined in patients with cancer and human immunodeficiency virus (HIV), yielding mixed results. There are studies reporting a stabilization of CD4+ T lymphocytes after psychotherapeutic interventions (Creswell et al., 2009, Petrie et al., 2004, Sherman et al., 2000); however, CD4+ and CD8+ T lymphocytes were not affected in other studies (Antoni et al., 2006, Carrico et al., 2005, Hosaka et al., 2000).

Furthermore, we know that effective psychotherapy with Narrative Exposure Therapy (NET) can reverse the increased level of DNA strand breaks observed in individuals with PTSD compared to controls (Morath et al., in press). NET is a trauma-focused treatment approach for PTSD, developed for survivors of war and torture (Schauer et al., 2011a). Its efficacy has been proven in a number of randomized controlled trials in post-conflict regions (Ertl et al., 2011, Neuner et al., 2004b) and in Europe (Hensel-Dittmann et al., 2011, Robjant and Fazel, 2010).

The present study has two aims: 1) to extend the findings by Sommershof et al. (2009) in a larger sample of individuals with PTSD, trauma-exposed non-PTSD subjects and non-exposed controls and 2) to investigate whether the altered T cell distribution in individuals with PTSD can be reversed by psychotherapeutic treatment with NET. Individuals with PTSD were investigated before treatment and four and 12 months after the end of therapy and T cell differentiation subsets were analyzed. We hypothesized that the NET treatment group would show an increase in the proportions of CD45RA+CCR7+ naïve CD8+ as well as in the proportion of CD4+CD25+FOXP3+ Treg cells.

Section snippets

Participants

Thirty-four individuals with PTSD and 43 non-PTSD controls were recruited through the Center of Excellence for Psychotraumatology, University of Konstanz, and public advertisements. Sixteen subjects with PTSD and 27 controls were also participants in a previous study by Sommershof et al. (2009). After the initial screening, individuals with PTSD (age 16–47 years) – refugees (13 Africa, 21 Middle East) with a history of war and torture experiences – were randomly assigned to either a treatment

The effect of traumatic stress and PTSD on T cell distribution at t0

There was no difference in the absolute cell number of lymphocytes (χ2 = .72; p = .70) between individuals with PTSD (median 1939, range 1249–2800), trauma-exposed individuals (median 1960, range 1301–2938), and non-traumatized controls (median 1815, range 1308–2965), but the percentage of total CD3+ T cells was significantly reduced in individuals with PTSD compared to non-traumatized controls (Table 3). Extending the results of Sommershof et al. (2009), we found a significant main effect for

Discussion

Extending the findings of Sommershof et al. (2009) in a larger sample, we found a decreased proportion of (CD45RA+CCR7+) naïve CD8+ T cells, an increased proportion of (CD45RA) memory CD8+ T cells, and a decreased proportion of CD4+CD25+FOXP3+ Treg cells at baseline in individuals with PTSD compared to controls with no or little trauma exposure. Moreover, trauma-exposed non-PTSD subjects showed a significantly lower proportion of naïve CD8+ T cells than non-exposed controls, and the number of

Contributors

J Morath, H Gola and A Sommershof contributed equally to this interdisciplinary work. J Morath and H Gola coordinated the psychological part of the study; A Sommershof coordinated the biological part of the study. J Morath recruited study participants, carried out a large number of the clinical interviews and psychotherapies, performed statistical analyses and drafted the manuscript. H Gola prepared the study, recruited study participants, carried out a large number of the clinical interviews

Conflict of interest

The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus membership; employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in

Role of funding source

This study was funded by the German Research Foundation (DFG) Research Unit FOR751 and the European Refugee Fund. The funding source had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Acknowledgment

We thank Frank Neuner for clinical supervision and treatment of patients and Heike Riedke, and Christiane Wolf for technical assistance.

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