The new genetics of bone marrow transplantation

Abstract

There is now little doubt that functional immune polymorphism exists and can exert a significant effect on the severity of immunologic disease. Studies in this area are driven by the belief that an understanding of the influence of immune polymorphism on immunologic disease will improve our ability to predict disease occurrence and severity. The usefulness of this information is necessarily limited, however, by the fact that an individual has a fixed genome. If an individual has an allele which predisposes to increased disease severity, there is little we can do, other than treat the disease in that individual in a more aggressive manner or attempt to find preventative therapies. There is, however, one unique immunologic disorder that is an exception to this rule. Graft-versus-host disease (GVHD), the major complication of bone marrow transplantation, is an immunologic reaction mediated, in large part, by donor T cells. It is unique in that it is the only immunologic disorder in which we can choose the genetics of the immune system causing the disorder. In this disease, more than any other, an understanding of the role of immune polymorphism is essential since we could hypothetically use this information to choose a donor whose T cells will not mediate GVHD of life-threatening severity. In this review, I argue that there is highly suggestive evidence that allelic polymorphism in non-MHC genes encoding mediators of the immune response exerts a very significant effect on the severity of GVHD and that typing for such allelic polymorphisms will in future be as important as MHC-typing in choosing an appropriate donor for bone marrow transplantation. Genes and Immunity (2000) 1, 316-320.

Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes

“…41,42 As examples, TNF and LTA expression levels and SNPs have been shown to correlate with an individual's susceptibility to, severity of and/or prognosis of diseases such as HIV, multiple sclerosis and cerebral malaria [43][44][45][46] and with prognosis or outcome of allograft transplantation and malignancies. 7,[47][48][49] Because of their linkage to HLA genes in the MHC and their biologic properties, it is speculated that TNF and/or LTA also may contribute to the etiology of MHC-associated autoimmune diseases such as systemic lupus erythematosus, 50,51 insulin-dependent diabetes mellitus, 52,53 myasthenia gravis 54,55 and rheumatoid arthritis. 56,57 Furthermore, TNF and LTA expression level phenotypes and individual SNP also have been associated with particular HLA types.…”

“…1,2 Initially identified for their cytotoxic and antitumor activity, 3,4 it is now well documented that these cytokines play critical roles in a variety of immunologic processes including inflammation, secondary lymphoid organ development and the control of intracellular pathogens. 1,[5][6][7] TNF and LTA are expressed in various different forms 2 and bind to multiple receptors to perform their functions. 2,8,9 The TNF and LT loci are tandemly arranged in the class III region of the human major histocompatibility complex (MHC) (Figure 1a) approximately 220 kb centromeric to the HLA-B locus.…”

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation

“…It has been suggested that polymorphisms in these immune effector genes may be as important as the degree of HLA mismatch in determining GVHD severity and that typing for such allelic polymorphisms may, in the future, be an important consideration when selecting an HSCT donor. 57 …”

Genetic variation and hematopoietic stem cell transplantation: expansion of the paradigm

“…Clinical and laboratory observations have focused on the HLA and KIR loci, and demonstrated the importance of single nucleotide differences, as single variants or components of haplotypes (1–3). Moreover, it is probable that additional variants, not of the class of HLA and KIR genes, contribute to the phenomena of acceptance or rejection of grafts, even between matched family members (4). For example, GVHD does occur between family members who match at the HLA loci (excluding identical twins).…”