Research Interests
I. Novel therapeutic strategies for EBV-positive lymphoid and epithelial cancers
Discovering action of different compounds in inducing lytic cycle of EBV in cancer cells and dissecting mechanistic pathways of viral lytic induction... More
II. Sequence analysis of EBV strains in EBV infection subjects and EBV+ malignancies
Development of novel assays in characterizing EBV strains to study distribution and inter-change of EBV strains among different body compartments and to discover pathogenic viral strains in malignancies... More
III. Role of adaptive and innate immune responses in the control of EBV
Longitudinal study of viral loads, humoral and CD8+ T cell responses in primary EBV infection in Chinese children and development of novel assays in polychromatic flow cytometry to dissect such immune responses...More
Clinical Cases
As Dr. Chiang is a clinical doctor in Queen Mary Hospital, department of paediatrics and adolescent medicine, the Chiang's lab has the advantage of obtaning clinical samples directly for the research proejects with consent of the patients' parents, which we own our utmost gratitude to. Our patients, from several month old infants to teenagers, mainly consist of Infectious mononucleosis (IM), Post-transplant lymphoproliferative disorder (PTLD) and Hemophagocytic lymphohistiocytosis (HLH) cases.
Post-transplant lymphoproliferative disorder (PTLD) is a severe disorder frequently attacking the organ transplant recipients with treatment of immunosuppressive drugs such as cyclosporine A, tacrolimus or anti-CD3 monoclonal antibody. Most cases of PTLD occur within several months after solid organ or bone marrow transplantation but some may be delayed to several years post transplantation. The majority of PTLD cases are characterized by unrestricted poly-, oligo-, or monoclonal B-cell proliferations but uncontrolled T-cell proliferation is also described. Epstein-Barr Virus has been confirmed etiologically associated with PTLD due to its presence in more than 90% of the PTLD cases. In the B-cell tumors EBV typically exhibits latency III state, in which full set of latent proteins EBNA-1,2,3A-3C, LMP1and LMP2 and EBV non-coding RNA EBERs 1 and 2 are expressed. This is the only in vivo example of EBV latency III infection caused by prolonged and profound immunosuppression of EBV-specific cytotoxic T cells.
In addition to the impaired EBV-specific T cells caused by immunosuppressive drugs, the presence of inhibitory cytokines such as interleukin-10 may contribute to development of PTLD as well. IL-10 not only reduces the capacity of monocytes and macrophages to induce T cell activation by inhibition of costimulatory molecules, but also interferes with the generation of interferon-alpha by dentritic cells, proliferation and cytokine secretion of T ells and natural killer cells.
Treatment of PTLD often starts with reduction of immunosuppressive drugs at the expense of increased risk of rejection of transplanted organs. A more promising therapy involves infusion of functional EBV-specific cytotoxic T cells into the patients, which supports the essential role of CD8+ T cells in control of EBV infection from another perspective.
In summary, PTLD is a life-threatening disease resulting from uncontrolled EBV-infected B cells due to impaired EBV-specific T cells by immunosuppressive drugs. It may serve as a good model to study what happens when the EBV-specific T cells are suppressed.
Infectious mononucleosis (IM) was first descreibed by Sprunt and Evans almost 100 years ago. In 1960s, it was confirmed to be an acute but self-limiting diseases caused by primary EBV infection with typical clinical characteristics of high fever, sore throat, symmetrical posterior cervical and postauricular lymphadenopathy, and elelid edema. Histological evidence of IM includes EBV infected B cells accompanied by lymphocytosis. This disease frequenctly attacks children, teenagers and even young adults. Recently, Sauce et,al. claimed that in IM patients the EBV-specific CD8+ T cells has long term defect in IL-15 secretion that may reulst in EBV associated malignancies such as Hodgkin's lymphoma.
Since that IM is usually a severe but self-limiting disease without need of antiviral therapy and that majority of the patients recover spontaneously within weeks after onset of symptoms, it serve as an ideal model to study EBV primary infection and the coevolving host immunity without the interference of treatment effects. In fact, most studies on evolution of EBV lytic- and latent-antigen specific T cell responses from primary infection to long term persistent phase were performed in IM patients.
Haemophagocytic lymphohistiocytosis (HLH), also referred to as heamophagocytic syndrome (HPS) is a collective syndrome, a big umbrella of hyperinflammatory disorders rather than a single blood disease, presenting in a variety of associated conditions among patients with either certain genetic deficiencies or virus infections. Major symptoms include inflammatory responses such as fever and rash, pancytopenia, splenomegaly, enlarged liver and lymph nodes, weight loss and even central nervous system problems like seizures, ataxia and hemiplegia.
Haemophagocytosis means phagocytosis by over-activating macrophages of erythrocytes, leukocytes, platelets and their precursors, which is mostly directed by the cytokine storms resulting from lymphocytic disorders. T cells, particularly CD8+ cells are usually considered as the major cause, while NK cells and B cells are reported to be the troublemakers in some minor cases as well.
There are primary and secondary HLH, which share similar symptoms yet different causes. Primary HLH, also called familial HLH occurs in approximately 1 in 50,000 individuals worldwide, which may be caused by mutations in any of several genes. These genes provide instructions for making proteins that help destroy or deactivate lymphocytes that are no longer needed. Secondary HLH, also called sporadic HLH, is the case we are trying to deal with. The patients usually develop the diseases after primary EBV infection or other viral infections. These patients probably do not have the mutations in their genome, but it is still possible that there are genetic polymorphism of these genes, making them more vulnerable to EBV infection compared to the majority of the healthy EBV-carriers. The clear pathogenesis and effective treatment remain to be studied.
Publications List
Five representative publications of the recent five years: (*Corresponding author)
Kwok H, Chan KW, Chan KH, Chiang AKS. Distribution, Persistence and Interchange of Epstein-Barr Virus Strains among PBMC, Plasma and Saliva of Primary Infection Subjects. PLoS ONE 10(3), 2015
KF Hui, YY Leung, PL Yeung, Jaap Middelorp and AKS Chiang. Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines. Br J Cancer, 2014
KF Hui and AKS Chiang. Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism. Int J Cancer 135: 2950-61, 2014
KF Hui, BHW Lam, Dona N Ho, GSW Tsao and AKS Chiang. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol Cancer Ther. 12:747-58, 2013
Hui KF, Ho DN, Tsang CM, Middeldorp JM, Tsao GSW, Chiang AKS*: Activation of lytic cycle of Epstein-Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma. Int J Cancer 131: 1930-1940, 2012
Kwok H, Tong AH, Lin CH, Lok S, Farrell PJ, Kwong DL, Chiang AKS*: Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. PLoS One 7: e36939, 2012
Ning RJ, Xu XQ, Chan KH, Chiang AKS*: Long term carriers generate Epstein-Barr virus (EBV)-specific CD4+ and CD8+ polyfunctional T cell responses which show immunodominance hierarchies of EBV proteins. Immunology 134: 161-171, 2011
Hui KF, Chiang AKS*: Suberoylanilide hydroxamic acid induces viral lytic cycle in Epstein-Barr virus-positive epithelial malignancies and medicates enhanced cell death. Int J Cancer 126: 2479-2489, 2010
Five representative publications beyond the recent five years: (*Corresponding author)
Wong OH, Huang FP, Chiang AKS*: Differential responses of cord and adult blood-derived dendritic cells to dying cells. Immunology 116: 13-20, 2005
Tso HW, Lau YL, Tam CM, Wong HS, Chiang AKS*: Association of IL12B polymorphisms with tuberculosis in Hong Kong Chinese. J Infect Dis 190: 913-919, 2004
Chiang AKS, Wong KY, Liang ACT, Srivastava G: Comparative analysis of Epstein-Barr virus gene polymorphisms in nasal T/NK-cell lymphomas and normal nasal tissues: Implications on virus strain selection in malignancy. Int J Cancer 80: 356-364, 1999
Chiang AKS, Chan ACL, Srivastava G, Ho FCS: Nasal T/natural killer (NK)-cell lymphomas are derived from Epstein-Barr virus-infected cytotoxic lymphocytes of both NK- and T-cell lineage. Int J Cancer 73: 332-338, 1997
Chiang AKS, Tao Q, Srivastava G, Ho FCS: Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease. Int J Cancer 68: 285-290, 1996