Genetic Determinants of Outcome in Allogeneic Bone Marrow Transplantation

Shanmugapriya, S (2007) Genetic Determinants of Outcome in Allogeneic Bone Marrow Transplantation. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.

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This work was aimed at identifying the significant markers other than HLA that could better predict immunological complications after HLA identical sibling allogeneic bone marrow transplantation in patients with β thalassemia major. One hundred and two β-thalassemia patients who underwent allogeneic HSCT at our centre from 1995 to 2004 were included in this study. Of the 102 patients, ninety six (94%) patients achieved ANC >0.5 x 109/L. Ninety one (89%) patients achieved platelet count >20 x 109/l. Three had primary graft failure and 6 rejected their graft >100 days after transplantation. Of the 96 patients who could be evaluated for acute GVHD, it was observed in 54 (56%) patients: grade I in 14 (13.7%), grade II in 27 (26.5%), grade III in 5 (4.9%) and grade IV in 8 (7.8%). Other 83 patients who could be evaluated beyond day 100 after HSCT, nineteen of them (22.9%) developed chronic GVHD. Of these, 3 developed de novo chronic GVHD and 16 progressed to chronic GVHD from previous acute GVHD. Overall survival post-transplant was 76% at 5 years (Figure 5.1.5). Immune mediated complications and infections at day 180 post transplant period were found to be the major causes for transplant related mortality (TRM). Apart from the conventional risk factors like age and gender of the patient and donor, sex and ABO mismatched transplant, cell dose and Lucarelli class of thalassemia that were evaluated, several potential newer markers were also assessed for their impact in the outcome of HSCT. These include polymorphisms in the genes of 23 different pro-inflammatory (IL-1β, TNF-α, TNF-β, IL-6 and IFN-γ), anti-inflammatory (TGF-β, IL-10, IL-1Ra, NO), other immunoregulatory (estrogen receptor, vitamin D receptor, CTLA-4, FOX-P3) and host defense (FcγRIIa, FcγRIIIa and NOD-2) polymorphisms on the occurrence of immune immediate complications like rejection, acute and chronic GVHD and infections were evaluated. Donor age >10 years was found to increase the risk of rejection. Recipient age >10 years, sex mismatched transplant and female donor to male recipient sex mismatched transplant increased the risk of acute GVHD. Previous acute GVHD was the main factor found to increase the occurrence of chronic GVHD. These results were consistent with the reported literature. Recipient IL-10 -1082 G allele was found to delay the recovery of ANC. Absence of IL-10 and TGF-β genotypes (haplotype: IL-10 -819 C, -592 C, dTGF-β codon 10 T/T, 25 G/G and dTGF-β codon 10 T/C, 25 G/G) associated with higher levels of IL-10 and TGF-β in the donor was associated with a 5-7 fold higher risk of rejection. These results suggest a role for these cytokines in inducing tolerance after HSCT. IL-1β -511 T/T genotype in the recipient which is associated with higher levels of this pro-inflammatory cytokine was found to increase the risk of grade 2-4 acute GVHD. IFN-γ +874 T/T genotype of the donor also associated with higher levels of inflammatory cytokine was found to increase the risk of grade 2-4 and grade 3-4 acute GVHD. Genotypes of IL-6 in recipients (IL-6 -176 C/C) and nitric oxide (dNOS-3 +894 T/T) in donors associated with lower levels was found to increase the risk of grade 2-4 acute GVHD. These results indicate for the first time the possible role of IL-6 and NO in ameliorating acute GVHD after allogeneic HSCT. None of the genotypes of pro-inflammatory and anti-inflammatory markers was found to increased risk or play a protective role in the occurrence of bacterial or viral infection at day 180 post-transplant period. IFN-γ +T/T genotype associated with higher levels was found to increase the risk of fungal infections at day 180 post-HSCT. These results of association between fungal infection and genotypes associated with increased level of inflammatory cytokines in this study could not be explained. Polymorphism in the FcγRIIa gene associated with decreased binding affinity for IgG2 conferring reduced phagocytic role for the neutrophils (FCγRIIa +4481 G allele) was found to increase the risk of bacterial infection in early period after transplant. Factors associated with increased risk of severe acute GVHD were found to be associated with poor overall survival. Role of IL-10 -819 T/T genotype of recipient reducing the overall survival rate could not be explained. Analysis of these genotypes role in development of toxicities due to conditioning regimen might be useful to decipher their impact on overall survival after HSCT. Our results enlighten the role of immunoregulatory factors (inflammatory and host defense genotypes) other than HLA in the outcome of HLA identical sibling HSCT. Due to the absence of direct evidence on the functional role of vitamin D receptor and FOX-P3 genotypes on pathophysiology of inflammatory responses, the role of these markers in the outcome of HSCT could not be explained. This is perhaps the first comprehensive study to evaluate the role of a large number of immunogenetic markers with engraftment/graft rejection, acute and chronic GVHD, bacterial, viral and fungal infections and overall survival in HLA identical sibling transplant in a cohort of patients with a single non-malignant genetic disorder. This work has helped in furthering our understanding of the role of immunogenetic factors in affecting the outcome of allo HSCT. Such information may become useful in selecting the best donor in unrelated transplants and also in designing therapeutic strategies to improve the outcome of allo-HSCT. CONCLUSIONS: This doctoral work has analyzed the role of clinical and genetic characteristics in the recipient and donor that can affect the outcome of HSCT. All patients included in the study had beta thalassemia major. They received two different conditioning regimens but uniform GVHD prophylaxis containing cyclosporine and short course methotrexate and an unmanipulated bone marrow graft. Our results show that the HLA-A9 allele and functional polymorphisms in the pro-inflammatory (IFN-γ +894T, IL-1β-511C, IL-6 -174C), anti-inflammatory (TGF-β codon 10T, codon 25G, IL-10 -1082 A, -819T, -592A, IL-1RA*2/2) and other host defense molecules (FcγRIIa +4481G) along with the conventional risk factors like recipient age, donor age, sex mismatched transplants (female donor to male recipient) influence the outcome of HSCT. Polymorphisms in the genes of NOS-3 and FOX-P3 postulated to modulate the immune response, which have not been previously studied, were also found to impact the outcome of HSCT. Future studies should be aimed at functional and patho-physiological role of these polymorphisms in these and additional genes coding for other immunomodulatory molecules such as the vitamin D receptor, estrogen receptor, FOXP3 and CTLA-4 with regard to their role in influencing outcome of HSCT. HIGHLIGHTS OF THIS DOCTORAL WORK: 1. This thesis is the first study that has evaluated the impact of genetic markers other than HLA on a large cohort of patients with a single non-malignant genetic disorder (β thalassemia) treated with a uniform protocol. This provides an opportunity to eliminate the role of disease related variables in the outcome and assess host-graft interactions. 2. The data from this thesis work shows for the first time the following correlations: a. The risk of rejection and IL-10 and TGF-β genotypes of donor. b. The risk of rejection and KIR genotype matching in patient and donor. c. The risk of acute GVHD (grades 2-4 and 3-4) and IFN-γ genotypes (IFN-γ +874 T/T) of donor. d. The risk of acute GVHD grade 2-4 and NOS-3 genotypes (NOS-3 +894 T/T) of donor and IL-1β -511 T/T genotypes of recipient. 3. This is the first study that has comprehensively shown the allele frequencies of a total of 15 gene polymorphisms occurring in a total of 11 immunoregulatory molecules (IL-1β, IL-1Ra, TNF-α, TNF-β, IL-6, IL-10, TGF-β, IFN-γ, NOS-3, FcγRIIa and FcγRIIIa) in the Indian population and compared them with that of other populations including Caucasians, African Americans, Japanese and Chinese.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Genetic Determinants, Outcome, Allogeneic Bone Marrow Transplantation.
Subjects: MEDICAL > Immunohaematology Blood Transfusion
Depositing User: Subramani R
Date Deposited: 18 Jan 2022 07:10
Last Modified: 18 Jan 2022 07:10

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