Μechanisms of alloresponse in allogeneic transplantation

Haema 2016; 7(2): 127-134

by Panagiotis Tsirigotis, Maria Atta, Konstantinos Girkas

2nd Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, General Hospital “Attiko”, Athens, Greece

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HsCT) provokes an immune response of the donor against host and vice versa. In the setting of human leukocyte antigen (HLA)-identical allo-HsCT, donor T-cells react against disparate host minor histocompatibility antigens (mHAgs). Alloreactive donor t-cells recognize peptides derived from host mHAgs presented in the context of self- HLA. In the setting of HLA-mismatched allo-HsCT, two non-mutually excluded hypotheses have been proposed. According to high determinant density theory, alloreactive T-cells recognize host-HLA independent of peptide. Despite the low affinity of alloreactive cells the high density of host-HLA present in immunological synapse results in high avidity ligation and therefore promotes immune activation. According to multiple binary complex theory, alloreactive donor T-cells recognize host peptide in the con- text of host-HLA with strong affinity due to mechanism of molecular mimicry. Donor T-cells with host alloreactivity are present only in the pool of naïve T-cells in the setting of HLA-identical allo-HsCT, while alloreactive T-cells are present in both pools of naïve and memory T-cells in cases of HLA-mismatched transplantation. Allorecognition of alloantigen is mediated through direct and indirect pathways. Antigenic peptides derived from the host are presented to donor alloreactive cells by host dendritic cells (DCs) or by donor DCs in the case of direct and indirect allorecognition pathway respectively. Allore- sponse mimics immune reactivity against pathogens in the case of HLA-identical transplants, while it is more complex and deviates from classical patterns in the case of mismatched transplantation. Alloreactive donor T-cells are present in extremely low numbers in the peripheral blood (PB) of un-immunized (against the recipient) donors in the setting of HLA-identity, while 1% to 10% of PB donor T-cells are alloreactive against the host in cases of mismatched transplantation. Calcineurin inhibitors display significant efficacy in graft versus host disease (GVHD) prevention in HLA-identical transplants but are ineffective in HLA-disparate transplantation.