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The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound deficits in immune function that lead to increased morbidity and mortality after bone marrow transplantation (BMT). We investigated a mechanism of T-cell immunodeficiency in response to mitogen or alloantigen in an experimental model of acute GVHD by analyzing the roles of two immunosuppressive moieties: interferon gamma (IFN-gamma) and nitric oxide (NO). Splenocytes from mice with GVHD did not proliferate either to the T-cell mitogen, concanavalin A (Con A), or to host alloantigens, but only mitogen- activated cultures produced increased levels of NO. The abrogation of NO synthesis with LG-mono-methyl-arginine (NMMA) restored mitogen- induced proliferation but not the response to host antigens. The mechanism of impared proliferation to mitogen was dependent on IFN- gamma because blockade of this cytokine in culture inhibited NO production and restored proliferation to Con A to levels similar to those in transplanted control mice without GVHD. NMMA did not substantially reduce IFN-gamma levels, demonstrating that NO acted distally to IFN-gamma in the pathway of immunosuppression in response to mitogen. Furthermore, the prevention of IFN-gamma production in vivo after allogeneic BMT, by transplantation of polarized type 2 donor T cells (secreting interleukin-4 but not IFN-gamma), also prevented NO production and restored splenocyte responses to mitogen. Our data demonstrate the existence of NO-dependent and NO-independent pathways involved in suppression of T-cell proliferation during acute GVHD. Excess NO synthesis appears to be one mechanism by which IFN-gamma induces immunodeficiency after allogeneic BMT.

Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as important effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (slg+) B cells was observed in GVHD spleens isolated 2 weeks after transplant. However, proliferation of these cells in response to LPS was suppressed by more than 35-fold. Activated GVHD splenocytes secreted large amounts of TNF- alpha and NO in culture. Neutralization of TNF-alpha with anti-TNF- alpha antibody (Ab) both abrogated NO production and restored LPS- induced proliferation of B cells to levels found in non-GVHD control mice. The specific inhibition of NO synthesis with LG-monomethyl- arginine (NMMA) restored splenocyte responses but did not significantly reduce TNF-alpha levels, showing that TNF-alpha per se did not cause immunosuppression. These data show that, during GVHD, induction of the NO pathway is an important mechanism that mediates B-cell hyporesponsiveness to LPS and that this pathway is induced by TNF-alpha.

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What ' s known on the subject? and What does the study add? Previously, rates of potency preservation with or without external beam radiation and/ or hormone therapy have been published with smaller series and limited follow-up. The study provides greater numbers and longer follow-up giving patients and clinicians a better appreciation of the true potency preservation rates in this population and how various factors such as age, hormone use and external beam affect those rates. OBJECTIVES• To assess potency preservation in men following brachytherapy for prostate cancer with or without external beam radiation therapy (EBRT) and/or androgen deprivation therapy (ADT).• To evaluate the factors that signifi cantly impact this rate. PATIENTS AND METHODS• In all, 1063 potent men with T1 -T3 prostate cancer were treated from 1990 to 2007 with seed implantation alone ( 103 Pd or 125 I) (69.6%) or combined modality treatment consisting of a partial dose 103 Pd implant followed 6 -8 weeks later by EBRT (45 Gy, prostate/seminal vesicles only) (30.4%). ADT was used in 49.1% of cases (range 1 -27 months).• Patients were required to have a minimum of 2 years follow-up and to be off ADT for a minimum of 1 year.• Erectile function was assessed prior to seed implantation and at each follow-up visit using the physician-assigned Mount Sinai Erectile Function Score (MSEFS): 0, unable to have erections; 1, erections insuffi cient for intercourse; 2, suboptimal erections but suffi cient for intercourse; 3, normal erectile function. Potent was defi ned as a score of greater than or equal to 2 with or without use of a phosphodiesterase type 5 inhibitor.• The potency rate was calculated using actuarial methods with comparisons tested by log-rank and Cox regression analysis. RESULTS• The 5-year and 10-year actuarial rate of potency preservation was 68.0% and 57.9%, respectively, at last follow-up.• On multivariate analysis, 5-and 10-year potency was 87.6% (79.5%) for men younger than 60, 68.0% (57.5%) for age 60 -70, and 42.2% (31.0%) for men older than 70 ( P < 0.001).• Pretreatment MSEFS of 2 had a potency rate of 51.7% (37.2%) vs 74.2% (65.2%) for an MSEFS of 3 ( P < 0.001).• There was a 75.8% (62.6%) potency rate without ADT vs 60.0% (53.0%) with ADT ( P < 0.001).• Five-year potency was 76.4% for implant alone, 71.0% for implant with EBRT, 62.2% for implant with ADT, and 57.9% for implant with EBRT and ADT ( P < 0.001). CONCLUSION• Increasing initial age at implant, diminished pretreatment erectile function and the use of combination therapy with EBRT and/or ADT signifi cantly increases erectile dysfunction following brachytherapy. KEYWORDSprostate cancer , brachytherapy , potency , androgen deprivation Study Type -Therapy (case series) Level of Evidence 4