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Cell Therapy Confers Protection from Immunodeficiency-Associated Pulmonary Hypertension and Prevents Activation of Right Ventricular Fetal Gene Program

Mark Nicolls

C. Long

K. Amber

Rasa Tamosiuniene


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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Nicolls M.R.1, Long C.2, Amber K.2, Tamosiuniene R.1

1. VA Palo Alto/Stanford University, Stanford, CA, USA
2. University of Colorado, Denver, CO, USA

BACKGROUNDFor over 40 years, autoimmune phenomena have been known to be associated with pulmonary arterial hypertension (PH). There is emerging evidence that autoimmune inflammation may trigger and propagate PH. Certain PH conditions have altered T cell subsets that may contribute to immunoregulatory defects. We recently reported that T cell-deficiency in athymic (AT) animals severely exacerbates experimental PH in outbred animals. To test whether immune reconstitution prevents PH in inbred AT animals, unfractionated syngeneic splenocytes given as a cellular therapy, were administered prior to vascular endothelial growth factor receptor (VEGFR) blockade. Protection was assessed by echocardiography (ECHO), pulmonary hemodynamics, and RV/LV+S. Given that reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts, we sought to determine whether immune cell therapy prevented activation of this pathway.

METHODSAT nude rats, deficient in T cells, were given a single dose of SU5416 (SU;20mg/kg i.p.) which induces severe PH at room air in these animals. Control AT animals were treated with vehicle only (carboxymethylcellulose). A group of AT rats were given 20 x 106 spleen cells i.p. (from syngeneic euthymic nude donors) 7d prior to SU. Cardiac function was assessed at 10d and 21d by 2D ECHO. Pulmonary hemodynamics and RV/LV+S were obtained on d21. To assess fetal genes, the expression of a-myosin heavy chain (a-MHC), b-myosin heavy chain (b-MHC), sarcoplasmic reticulum Ca2+-ATPase (SERCA), brain natriuretic factor (BNP), a-skeletal actin (SkACT), and atrial natriuretic factor (ANP), was determined by real-time reverse transcription polymerase chain reaction (RT-PCR).

RESULTSBy ECHO, SU treatment caused a reduction in the RV fractional shortening, a thickening of the RV free wall, and an acceleration of the peak flow across the PA valve, consistent with increased PA pressures. These effects were attenuated by cell therapy. Right heart catheterizations showed the following RVSPs: AT (17±2mmHg), AT+SU (42±10mmHg) and AT+SU+cells (25±7mmHg). RV/LV+S measurements were: AT (0.21±0.1), AT+SU (0.43±01) and AT+SU+cells (0.22±0.1). Fetal gene expression was consistent with severe injury pattern that was significantly attenuated by cell therapy.

COMMENTS AND CONCLUSIONSThis is the first study to show that syngeneic immune cell therapy in PH animals prevents severe PH and the activation of RV fetal genes associated with failing and injured hearts. Inflammatory injury exacerbated by the absence of T-cells is consistent with autoimmune phenomena. We are currently fractionating T cell populations to determine which lymphocyte subsets (e.g. CD4+CD25+) contain the putative regulatory cell population normally responsible for preventing PH. Treating  PH with cellular therapy suggests that immunomodulation may be an exciting therapeutic approach in autoimmune-associated PH.

Cell Therapy Confers Protection from Immunodeficiency-Associated Pulmonary Hypertension and Prevents