Allogeneic hematopoietic stem cell transplantation (HSCT) Introductory Note
Since its discovery about half a century ago, the human leukocyte antigen (HLA) system has been shown to play a central role in the networks governing both adaptive and innate immunity, relevant in different clinical settings including transplantation, cancer, infectious diseases and autoimmunity. Inter-individual gene polymorphism is a hallmark of the HLA system, with over 3000 class I and class II alleles identified, a number that is continuously increasing. This poses important challenges regarding both the structural characterization of polymorhpic HLA antigens and the evaluation of their functional significance. The HSR Immunogenetics Laboratory has performed pioneer work in this area, by exploiting the combined facilities and expertise in HLA diagnostics and research. The main goal of the group is to unravel the role of polymorphic HLA antigens in the clinical setting of allogeneic hematopoietic stem cell transplantation, with regards to adverse clinical effects (graft versus host disease and rejection) versus beneficial ones (graft versus tumor activity), and to translate this knowledge into clinical practice.
Research Activity
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for a variety of neoplastic and inborn genetic diseases of the hematopoietic system, occurring with considerable frequency in young adults and children. The power of this treatment modality for the cure of onco-hematologic disorders including leukemia and lymphoma, relies largely on cellular immunotherapy mediated by alloreactive donor T cells against polymorphic patient-specific human leukocyte antigens (HLA) or minor histocompatibility antigens (graft versus leukemia; GvL). On the other hand, the same polymorphic structures are also targets of graft versus host disease (GvHD) and graft rejection, two major clinical complications post-transplantation.
The main goal of the group is to unravel the role of HLA and other polymorphic immune-related molecules in promoting GvL versus GvHD and rejection after allogeneic HSCT, and to translate this knowledge into clinical practice.
The ongoing research projects in the laboratory are:
Molecular characterization of alloreactive T cell epitopes determining non-permissive human leukocyte antigen DP mismatches in allogeneic HSCT
Characterization of leukemia immunoediting in response to allogeneic HSCT
Molecular characterization of alloreactive T cell epitopes determining non-permissive human leukocyte antigen DP mismatches in allogeneic HSCT
HLA-DP antigens are appealing targets of GvL, because their expression is restricted to the recipient’s hematopoietic system, and because they are frequently mismatched in the setting of unrelated HSCT, due to weak linkage disequilibirium with other HLA class II loci. Our group has recently defined an algorithm of non-permissive HLA-DP disparity, on the basis of T cell alloreactivity patterns, and shown that non-permissive mismatches were associated with significantly impaired overall survival after unrelated HSCT (Crocchiolo et al., Blood 2009). We are now seeking to identify the molecular structure of the relevant T cell epitope, by mapping studies using alloreactive HLA-DP specific T cell clones and site-directed HLA-DP mutants of HLA-DP.
Characterization of leukemia immunoediting in response to allogeneic HSCT
The curative effect of allogeneic HSCT in the treatment of onco-hematologic disorders such as leukemia and lymphoma, is largely based on immunosurveillance of residual neoplastic cells by alloreactive donor T cells. Our group has recently demonstrated that leukemia cells frequently evade this mechanism by selective loss of the patient-specific haplotype in leukemic blasts relapsing after HLA-mismatched allogeneic HSCT (Vago et al., N Engl J Med 2009). Using genome-wide SNP analysis of leukemic blasts at diagnosis or in relapse after allogeneic HSCT, we will now seek to systematically characterize the role of leukemia immunoediting in response to cellular therapy, both in patients and in a murine model of allogeneic HSCT in mouse-human chimeras.
|
