IGHG Genes (GM Allotypes) and Anti-CMV (UL70) Antibody Responses as Prognostic Markers for Chronic Graft-Versus-Host-Disease

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Chronic graft-versus-host disease (cGVHD) remains a major obstacle to improving outcomes in hematopoietic cell transplant (HCT) recipients. There is a paucity of biomarkers that could identify patients before the development of the disease. Genetic markers of cGVHD identified by the genome-wide association studies (GWAS), which do not interrogate GM (γ marker) alleles, have not been replicated. There is excellent rationale for the involvement of immunoglobulin GM genes in the etiopathogenesis of cGVHD. GM alleles modulate an immunoevasion strategy of cytomegalovirus (CMV), a frequent viral infection after HCT, which, despite improvements in antiviral therapies, can lead to life-threatening CMV disease in ~10 % of HCT recipients. CMV expresses three decoy Fcg receptors (FcgRs), which interfere with Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), a potent host immunosurveillance mechanism against viruses. Interestingly, GM alleles modulate this viral strategy: IgG antibodies expressing different GM alleles bind differentially to the decoy FcgRs. GM genes also contribute to the interindividual differences in the magnitude of humoral immunity to CMV. Furthermore, GM genes have been implicated in the immunobiology of scleroderma, an autoimmune disease whose clinical features resemble that of cGVHD. Based on these observations—and the results of our preliminary studies that showed higher levels of antibodies to CMV UL70 in non-cGVHD subjects than in those with cGVHD—we hypothesize that GM alleles and antibody responses to CMV proteins are prognostic markers for cGVHD. The following specific aims will test our hypothesis: (1) Determine if the distribution of GM alleles differs significantly between cGVHD and non-cGVHD patients. Serum/plasma samples from HCT recipients who developed cGVHD and from those who did not— obtained from the BMT CTN 0201 participants—will be genotyped for several GM alleles. We will determine whether the alleles of the highly polymorphic GM loci serve as prognostic genetic markers of cGVHD; (2) Determine if the magnitude of anti-CMV (UL70) antibody responses differs significantly between cGVHD and non-cGVHD patients, and if GM alleles contribute to the interindividual differences in these responses. The results of our preliminary studies suggest that anti-UL70 antibodies might play a protective role in the development of cGVHD. It is important to replicate this finding in an independent study population. We will measure the level of anti-UL70 antibodies in BMT CTN 0201 specimens and determine if the level of these antibodies is influenced by GM alleles. There is high likelihood that the results of this investigation will identify much-needed prognostic markers for cGVHD. Furthermore, they may provide targets for immunotherapy of this disease. Recent studies from a murine model of HCT show that CMV reactivation can be prevented by the infusion of strain-specific anti-CMV antibodies. Perhaps infusion of monoclonal anti-UL70 antibodies could similarly prevent CMV reactivation, a life-threatening complication in some HCT recipients.