Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality

Intestinal immunoglobulin A (IgA) is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute graft-versus-host disease (GvHD), we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation (allo-SCT) from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD Lerner stage 0: 131+/-8 IgA+ plasma cells/mm2; stage 1-2: 108+/-8 IgA+ plasma cells/mm2; stage 3-4: 89+/-16 IgA+ plasma cells/mm2; P=0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (P=0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after allo-SCT were predictive of relapse and relapse-related mortality (RRM): pts with low IgA+ cells had a 15% RRM at 2 and at 5 years, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (hazard ratio =2.7; 95% confidence interval: 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD

Analyse IgA-exprimierender Zellen in intestinalen Gewebeproben nach allogener Stammzelltransplantation und deren Bedeutung beim Vorliegen einer Graft-versus-Host-Erkrankung

Die bisherige Diagnostik zur Immunrekonstitution stammzelltransplantierter Patienten fokussierte sich in erster Linie auf Analysen im peripheren Blut. In dieser Arbeit wurden Gewebeproben aus unterschiedlichen Darmabschnitten stammzelltransplantierter Patienten untersucht und es erfolgte eine Analyse der IgA-exprimierenden Zellen mittels Immunhistochemie. Für das untersuchte Patientenkollektiv zeigte sich eine Abnahme der Zelldichte mit steigendem histopathologischen Schweregrad der GvHD nach Lerner in allen untersuchten Darmabschnitten. Darüber hinaus wiesen die Ergebnisse auf eine mögliche prognostische Aussagekraft der Zelldichte hin: Die Mortalität durch ein Rezidiv der malignen Grunderkrankung war – unabhängig vom Auftreten einer GvHD – bei einer Zellzahl oberhalb der medianen Zelldichte signifikant mit geringeren Überlebensraten assoziiert. Der Zusammenhang stellte sich bezüglich der TRM umgekehrt dar. Auf dieser Basis lässt sich die Hypothese aufstellen, dass sich die intestinalen IgA-exprimierenden Zellen als Indikatoren der Alloreaktion eignen und somit eine prognostische Aussagekraft besitze

Intestinal IgA positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both, graft-<i>versus-</i>host disease and relapse related mortality

Intestinal IgA is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute GvHD, we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD lerner stage 0: 131+/- 8 IgA+ plasma cells/mm2; stage 1-2: 108 +/-8 IgA+ plasma cells/ mm2; stage 3-4: 89+/-16 IgA+ plasma cells/ mm2, p 0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (p = 0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after SCT were predictive of relapse and relapse related mortality (RRM): Pts with low IgA+ cells had a 15% RRM at 2 and at 5 yrs, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (HR 2.7 (95% CI 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD