Post-transplant lympho proliferative disorder (PTLD) is an aggressive lymphoma afflicting 2-7% of all transplant recipients, with mortality rates as high as 87%. Many PTLD cases are associated with Epstein Barr virus transformation of B cells and tumor formation. In healthy adults, EBV antigens are presented to EBV-reactive T cells with appropriate costirnulation signals, resulting in T cell priming and activation. EBV-reactive T cells kill the tumor cells as they arise from the latently infected B cells. However, in PTLD, this protective response does not happen. We know that most PTLD patients are homozygous for the A allele at residue 847 of the interferon gamma (IFNg) gene (A/A genotype), and very few exhibit the T/T genotype associated with high cytokine production. Thus, the absence of high IFNg appears to contribute to PTLD. This is also true in the SCID-Hu PBL mouse model. TGF beta (TGFb) is associated with tumorigenesis and its production can be induced by immunosuppressive drugs used to prevent graft rejection. In addition, TGF beta and IFN gamma have antagonistic signaling pathways, and TGFb can functionally silence CTL from A/A and T/A, but not T/T, IFNg genotypes. TGFb appears to mediate its effects via APC, as APC exposed to TGFb and EBV can block EBV-reactive inflammatory responses. In transplantation, regulatory cytokines like TGF-beta, are usually associated with the beneficial effect of transplant acceptance. However, a detrimental effect of TGFb could be to prevent a functional anti-tumor response or to directly promote tumor growth. We hypothesize that TGFb contributes to PTLD through APC to block EBV-reactive CTL activity and may also directly promote tumor formation in patients with the A/A genotype for IFNg. We will use the SCID-Hu PBL mouse model to test these two possibilities. In Specific Aim 1, we will determine the requirement for TGFb in tumor formation. We will determine if neutralization of TGFb prevents tumor formation, and if the addition of TGFb to purified B cells allows tumor formation. In Specific Aim 2 we will determine if APC pre-exposed to TGFb can inhibit CTL activity in vitro and in vivo and whether these APC can promote tumor formation by B cells. The results from this pilot study will indicate whether TGFb is crucial to tumor formation in the SCID-Hu PBL mouse model.
NIH ExPorter
NIH ExPorter