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INCREASING SELF, A NEW CLUE IN THE IMMUNOSURVEILLANCE OF MYELOMA BY LICENSED NK CELLS.
Autores:
ALFREDO MINGUELA PURAS
,
MARIA VICTORIA MARTÍNEZ SÁNCHEZ
,
ISABEL LEGAZ PÉREZ
,
LOURDES GIMENO ARIAS
,
ANNA MROWIEC
,
JOSÉ ANTONIO CAMPILLO MARQUINA
,
MARÍA VICTORIA BERNARDO PISA
,
MANUEL MURO AMADOR
,
VALENTIN CABAÑAS PERIANES
,
JOSÉ LUIS FUSTER SOLER
,
ANA MARÍA GARCÍA ALONSO
,
JOSE MARIA MORALEDA JIMÉNEZ
,
MARIA ROCIO LÓPEZ ÁLVAREZ
,
Grupos de investigación:
[GI/IMIB/C006/2011] INMUNOLOGÍA E INMUNOTOLERANCIA EN TRASPLANTES Y ENFERMEDADES DE BASE INMUNOLÓGICA
[GI/IMIB/C061/2011] TRASPLANTE HEMATOPOYÉTICO / TERAPIA CELULAR
Comunicación:
Antecedentes:
Missing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands.
Métodos:
The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls.
Resultados:
Compared to controls, myeloma accumulates KIR2DL1-L2+L3- genotypes (2.8% vs. 13.2%, p?0.01, OR=5.29) and less diverse peripheral repertoires of NKc clones. Less diverse and weaker-affinity repertoires of iKIR2D/HLA-C licensing interactions increased myeloma susceptibility. Thus, the complete absence of conventional iKIR2D/HLA-C licensing interactions (KIR2DL1-L2+L3-/C2C2, 2.56% vs. 0.35%; P<0.05; OR=15.014), single-KIR2DL3+/C1+ (20.51% vs. 10.84%; P<0.05; OR=2.795) and single-KIR2DL2+/C1+ (12.82% vs. 4.9%; P<0.01; OR=5.18) interactions were over-represented in myeloma, compared to controls. Additionally, KIR2DL1-L2+L3- (20% vs. 83%, P<0.00001) as well as KIR3DL1- (23% vs. 82%, P<0.00001) genotypes had a dramatic negative impact on the three-year progression-free survival, particularly in patients with low-tumor burden. Remarkably, myeloma-PCs, compared to K562 and other hematological cancers, showed substantial over-expression of HLA-I (“increasing-self” instead of missing-self), including HLA-C, and mild expression of ligands for NKc activating receptors (aRec) CD112, CD155, ULBP-1 and MICA/B, which apparently renders myeloma-PCs susceptible to lysis mainly by licensed NKc. KIR2DL1-L2+L3-/C2C2 patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myeloma-PCs (4% vs. 15%; P<0.05, compared to controls).
Conclusiones:
These results support a model where immunosurveillance of no-missing-self cancers, e.g. myeloma, mainly depends on NKc licensing.
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