Session Type: Abstract Submissions (ACR)
Background/Purpose: Aggressive immunotherapy has shown modest effectiveness for pulmonary hypertension in anti-RNP Autoimmunity, but with high morbidity. We studied the ability of an ITGAM-targeted therapy that has been previously reported to have immunomodulatory properties to treat a model of this condition.
Methods: Following IACUC-approved protocols, study mice were adoptively transferred with splenic dendritic cells from anti-RNP-immunized syngeneic donor mice, and screened for elevations in serum Brain Naturietic Peptide (BNP) levels. Mice developing increased BNP levels received a single IV dose of the ITGAM-specific small molecule agonist Leukadherin-1 (LA-1), a chemically similar compound without ITGAM specificity (LA-C), or sterile PBS. Mice were then followed for BNP levels and/or underwent right heart catheterization to directly assess pulmonary circulation hemodynamics.
Results: The majority of splenic CD11c+ dendritic cells from anti-RNP+ donor mice express ITGAM by FACS. Treatment of these cells in vitro induces massive dendritic cell death, and prevents the development of adoptive transfer-induced lung disease. Mice receiving intact CD11c+ dendritic cells from anti-RNP donor mice develop substantial elevations in serum BNP levels, that correlate with increases in pulmonary pressures on right heart catheterization. Treatment of mice with established high serum BNP levels with LA-1 (but not controls) leads to rapid normalization of serum BNP levels and hemodynamic indices in 80% of study mice. No LA-1-induced toxicity was observed.
Conclusion: Adoptive transfer of ITGAM+ dendritic cells can induce pulmonary hypertension and ITGAM-targeted therapy can treat established pulmonary hypertension in a model of anti-RNP autoimmunity. These findings emphasize the potential importance of dendritic cells as mediators of tissue damage in anti-RNP autoimmunity, and raise the question whether the genetic associations of ITGAM with autoimmune disease risk could be mediated through effects on dendritic cells. LA-1 is a promising compound to develop for potential human trials.
E. L. Greidinger,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-itgam-cells-successfully-treats-a-model-of-anti-rnp-associated-pulmonary-hypertension/