Impact Of Patient/Donor Cytokine Genotypes On The Development Of Acute Graft Versus Host Disease (aGVHD) After Peripheral Blood Stem Cell Transplantation From An Identical Sibling
Authors: Kamel Azza M , Ebid Gamal TA , Gamil Abdullah , El-Fattah Raafat Abd , Mahmoud Hossam K , El-Mooti Mohammed Abd 
Published: October 2019

Abstract
In spite of prophylactic measures GVHD continues to be one of the serious complications that affect transplantation-related morbidity and mortality. We have previously reported a role of cytokines in the prediction of aGVHD (Kamel et al, 54th ASH Annual meeting, December 8-11.2012.Publicaion Number 1956. Nov 2012; 120: 195 and J Leuk 2013, 1:2 http://dx.doi.org/10.4172/jlu.1000111)
Apart from the triggering stimulus for cytokine production, the genotype may be a contributing factor to the actual level of the secreted cytokine. We hypothesized that the genotype of a given cytokine with its expected phenotype in patients and/or donors may impact the immune response contributing to the pathogenesis of aGVHD. We aimed to verify if the genotype of a given cytokine in patients and/or donors may help to predict the occurrence of aGVHD
The work was performed according to Helsinki declaration, the protocol was approved by the IRB of the NCI, Cairo University and an informed consent was obtained from all subjects.
The study cohort included 80 patient/donor pairs who received PBSCT from an identical sibling at Nasser Institute, MOH, Egypt in the period from December 2010 –December 2012. We determined the genotype of TNFα, TGFβ, IL10, IL6 and IFNγ by SSP typing using Cytokine Genotyping Tray REF CYTGEN (one Lambda, Inc, 21001 Kittridge st., Canoga Park, CA 91303 USA).
Patients were followed up for at least one year; development of GVHD was recorded.
Of the 80 cases, 23 developed acute GVHD, 9 developed chronic GVHD on top.The genotypes with the corresponding phenotype are presented in table (1).
TNFα was of the high producer genotype (G/A or A/A) in all patients and donors. IL6 was also of the high producer genotype (G/G or G/C) in all except one in each category which was low producer genotype (C/C). These two genes will not be discussed any further. TGFβ was of the low producer genotype (C/C G/C, C/C C/C, T/t C/C, or T/c C/C) in 22/23 patients who developed acute GVHD; the remaining patient had an intermediate producing genotype (T/C G/C). The corresponding figures for those who did not develop acute GVHD was 71/80 (88.75%) with low producing genotype, one with high producing genotype (T/C G/G) and seven with intermediate producing genotype (T/C G/C, C/C G/G or T/T G/C). All donors of patients who developed acute GVHD had the low producing genotype except one that showed an intermediate producing genotype (T/C G/C). The corresponding figures for donors of patients who did not develop GVHD included 51 (89.5%) with low producing genotype, two with high producing genotype (T/T G/G) and four with intermediate producing genotype. However, the difference did not achieve statistical significance for either patients or donors. For IL10 and IFN γ, the distribution of the various genotypes among patients/donors who developed was comparable to those who did not develop acute GVHD.Table 1Cytokine’s Genotypes and corresponding phenotypes of 80 patient/donor pair in relation to acute graft vs. host diseaseGeneGeno/Pheno-typePatientsDonorsGeneGeno/Pheno-typePatientsDonorsaGVHD 23 (100%)No GVHD 57 (100%)aGVHD 23 (100%)No GVHD 57 (100%)aGVHD 23 (100%)No GVHD 57 (100%)aGVHD 23 (100%)No GVHD 57 (100%)TNF-α 308H23 (100)56 (98.2)23 (100)56 (98.2)IL-10 -1082,-819,-592H4 (17.4)13 (22.8)2 (8.7)9 (15.8)L0 (0)1 (1.8)0 (0)1 (1.8)H/I5 (21.7)7 (12.3)2 (8.7)6 (10.5)TGF-β1 10, 25H0 (0)1 (1.8)02 (3.5)I9 (39)27 (27.4)15 65.2)29 (50.9)I1 (4.3)7 (12.3)1 (4.3)4 (7)L5 (21.7)10 (17.5)4 (17.4)13 (22.8)L22 (95.7)49 (85.9)22 (95.7)51 (89.5)IFN-γ +874H4 (17.4)6 (10.5)3 (13)11 (19.3)IL-6 -174H22 (95.7)53 (93)22 92.7)51 (89.5)I13 (56.5)36 (63.2)12 (52.2)32 (56.1)L1 (4.3)4 (7)1 (4.3)6 (10.5)L6 (26.1)15 (26.3)8 (37.7)14 (24.6)H: High, I: Intermediate, L: Low

Conclusion
The genotype of TNFα and IL6 are homogenous among Egyptian population; they cannot be used for discrimination between any studied disease conditions. TGFβ of high or intermediate producing genotypes are uncommon but mainly confined to patient/donor pairs with no GVHD; yet statistical significance was not achieved. IL10 and IFN γ genotypes of patients/donors are not associated with or predictive of acute GVHD. Taking in consideration the previous reports on the predictive value of both or either at the cytokine level including the work of the authors, it may be speculated that the genotype is not the main or the only predictor of the level of cytokine production in the setup of PBSCT.

Disclosures:
No relevant conflicts of interest to declare.