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HLA and drug hypersensitivity
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PATHOLOGY UPDATE 2010 ABSTRACTS
binding.2 In addition, a repository of missense mutations identified in patients with the rare familial immune deficiency syndrome, familial haemophagocytic lymphohistiocytosis (FHL) has proven invaluable in identifying perforin residues that result in either presynaptic protein instability or postsynaptic dysfunction at the level of the target cell membrane.3 Mutagenesis and modelling have recently allowed us to define the mechanism through which perforin forms transmembrane olgomers.4 The functional implications of certain common human perforin polymorphisms such as Ala91Val and much rarer mutations will also be discussed, particularly with respect to perforin’s role in human cancer susceptibility.5 References 1. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 2006; 6: 940–52. 2. Voskoboinik I, Thia MC, Fletcher J, et al. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 2005; 280: 8426–34. 3. Voskoboinik I, Thia MC, De Bono A, et al. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 2004; 200: 811–6. 4. Baran K, Dunstone M, Chia J, et al. The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity 2009; 30: 684–95. 5. Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I, et al. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci USA 2009; 106: 9809–14.
HLA AND TRANSPLANTATION – THE ROLE OF THE HISTOCOMPATIBILITY LABORATORY Frank T. Christiansen1,2 1 Department Clinical Immunology, PathWest, Royal Perth Hospital and 2School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia One of the main barriers to allogeneic transplantation is the recognition by the host’s immune system of foreign non-self histocompatibility antigen on the donor tissue. The major target for these alloresponses are the highly polymorphic HLA molecules, encoded within the major histocompatibility complex. In clinical practice the histocompatibility laboratory facilitates the selection of the most suitable allogeneic donor. In solid organ transplantation HLA matching provides an important parameter in donor selection. Prior sensitisation of the recipient with the development of donor-specific HLA antibodies is associated with increased risk of rejection and poorer graft outcome. New more sensitive solid-phase assays allow the detection of such antibodies not previously recognised by traditional crossmatch techniques, allowing for better donor selection and post transplantation monitoring. In HSC transplantation HLA matching is critical. Whilst the ideal donor remains the completely HLA matched family donor, the use of new techniques for high resolution HLA typing is now allowing the selection of suitable well matched unrelated donors from volunteer panels with similar outcome, resulting in the more widespread application of this life saving therapy. Any successful allogeneic transplant program requires an effective interaction between its histocompatibility laboratory, clinicians, scientists, donor coordinators, donor registries and transplant centres.
Pathology (2010), 42(S1)
HLA AND DRUG HYPERSENSITIVITY Brian D. Tait1, Mary Diviney2, Rhonda Holdsworth1, James McCluskey3 1 National Transplant Services, Australian Red Cross Blood Service, Melbourne, 2Victorian Transplantation and Immunogenetics Service, National Transplant Services, Australian Red Cross Blood Service, Melbourne, and 3 Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia Approximately 7% of individuals suffer from adverse drug reactions (ADR) some of which are life threatening. While ADRs can manifest in a variety of ways, approximately onethird are associated with hypersensitivity reactions (HR). The genomic era has created the means of elucidating the gene(s) involved in specific drug responses and permitting tailoring of individual drug therapy. Molecular typing has revealed three examples where HLA genes play a central role in the immune response to drug therapy. The outstanding example is the association of HLA-B*5701 in patients with a HR to the nucleoside analog reverse transcriptase inhibitor (NRTI) abacavir, which is used in the treatment of HIV positive and AIDS patients. The strong association with B*5701 necessitates HLA gene typing prior to treatment, with HLA-B*5701 positive patients being offered alternative therapy. The Royal College of Pathologists of Australasia (RCPA) in conjunction with the Australian and South East Asian Tissue Typing Association is currently running a quality assurance program to monitor laboratories performing this test. Other examples include the strong association of Stevens– Johnson syndrome and toxic epidermal necrosis (TEN) with HLA-B*1502, and treatment with the anti-convulsant drug carbamezepine in Han Chinese, Thais and Malays, and HLAB*5801 with the use of allopurinol for the treatment of hyperuricemia.
A NOVEL POPULATION OF REGULATORY CD4 T CELLS IS DEFICIENT AFTER STIMULATION BY AUTOANTIGEN IN TYPE 1 DIABETES James A. Dromey, Esther Bandala-Sanchez, Simone Reinwald, Bo Han Lee, Larissa Belov, Leonard C. Harrison The Walter & Eliza Hall Institute of Medical Research and Burnet Clinical Research Unit, The Royal Melbourne Hospital, Parkville, Victoria, Australia Regulatory T cells (Tregs) suppress pro-inflammatory immune responses and prevent autoimmune disease. Many types of Tregs have been described, the prototypic in mice defined as CD4 þ CD25 þ with high expression of the Foxp3 transcription factor. However, Fox P3 is not a reliable marker of human CD4 þ CD25 þ Tregs and Tregs activated by disease-associated antigens have not been well characterised. By comparing autoantigen-activated CD4 þ Tcell clones, we identified CD52 as a marker of suppressor clones. We then showed that high expression of CD52 on antigen-activated T cells identified a unique Treg population in human blood. CD52hi Tregs were not distinguished by markers of CD4 þ CD25 þ Tregs and did not require cell contact for suppressor function. Following activation by
PATHOLOGY UPDATE 2010 ABSTRACTS
binding.2 In addition, a repository of missense mutations identified in patients with the rare familial immune deficiency syndrome, familial haemophagocytic lymphohistiocytosis (FHL) has proven invaluable in identifying perforin residues that result in either presynaptic protein instability or postsynaptic dysfunction at the level of the target cell membrane.3 Mutagenesis and modelling have recently allowed us to define the mechanism through which perforin forms transmembrane olgomers.4 The functional implications of certain common human perforin polymorphisms such as Ala91Val and much rarer mutations will also be discussed, particularly with respect to perforin’s role in human cancer susceptibility.5 References 1. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 2006; 6: 940–52. 2. Voskoboinik I, Thia MC, Fletcher J, et al. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 2005; 280: 8426–34. 3. Voskoboinik I, Thia MC, De Bono A, et al. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 2004; 200: 811–6. 4. Baran K, Dunstone M, Chia J, et al. The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity 2009; 30: 684–95. 5. Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I, et al. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci USA 2009; 106: 9809–14.
HLA AND TRANSPLANTATION – THE ROLE OF THE HISTOCOMPATIBILITY LABORATORY Frank T. Christiansen1,2 1 Department Clinical Immunology, PathWest, Royal Perth Hospital and 2School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia One of the main barriers to allogeneic transplantation is the recognition by the host’s immune system of foreign non-self histocompatibility antigen on the donor tissue. The major target for these alloresponses are the highly polymorphic HLA molecules, encoded within the major histocompatibility complex. In clinical practice the histocompatibility laboratory facilitates the selection of the most suitable allogeneic donor. In solid organ transplantation HLA matching provides an important parameter in donor selection. Prior sensitisation of the recipient with the development of donor-specific HLA antibodies is associated with increased risk of rejection and poorer graft outcome. New more sensitive solid-phase assays allow the detection of such antibodies not previously recognised by traditional crossmatch techniques, allowing for better donor selection and post transplantation monitoring. In HSC transplantation HLA matching is critical. Whilst the ideal donor remains the completely HLA matched family donor, the use of new techniques for high resolution HLA typing is now allowing the selection of suitable well matched unrelated donors from volunteer panels with similar outcome, resulting in the more widespread application of this life saving therapy. Any successful allogeneic transplant program requires an effective interaction between its histocompatibility laboratory, clinicians, scientists, donor coordinators, donor registries and transplant centres.
Pathology (2010), 42(S1)
HLA AND DRUG HYPERSENSITIVITY Brian D. Tait1, Mary Diviney2, Rhonda Holdsworth1, James McCluskey3 1 National Transplant Services, Australian Red Cross Blood Service, Melbourne, 2Victorian Transplantation and Immunogenetics Service, National Transplant Services, Australian Red Cross Blood Service, Melbourne, and 3 Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia Approximately 7% of individuals suffer from adverse drug reactions (ADR) some of which are life threatening. While ADRs can manifest in a variety of ways, approximately onethird are associated with hypersensitivity reactions (HR). The genomic era has created the means of elucidating the gene(s) involved in specific drug responses and permitting tailoring of individual drug therapy. Molecular typing has revealed three examples where HLA genes play a central role in the immune response to drug therapy. The outstanding example is the association of HLA-B*5701 in patients with a HR to the nucleoside analog reverse transcriptase inhibitor (NRTI) abacavir, which is used in the treatment of HIV positive and AIDS patients. The strong association with B*5701 necessitates HLA gene typing prior to treatment, with HLA-B*5701 positive patients being offered alternative therapy. The Royal College of Pathologists of Australasia (RCPA) in conjunction with the Australian and South East Asian Tissue Typing Association is currently running a quality assurance program to monitor laboratories performing this test. Other examples include the strong association of Stevens– Johnson syndrome and toxic epidermal necrosis (TEN) with HLA-B*1502, and treatment with the anti-convulsant drug carbamezepine in Han Chinese, Thais and Malays, and HLAB*5801 with the use of allopurinol for the treatment of hyperuricemia.
A NOVEL POPULATION OF REGULATORY CD4 T CELLS IS DEFICIENT AFTER STIMULATION BY AUTOANTIGEN IN TYPE 1 DIABETES James A. Dromey, Esther Bandala-Sanchez, Simone Reinwald, Bo Han Lee, Larissa Belov, Leonard C. Harrison The Walter & Eliza Hall Institute of Medical Research and Burnet Clinical Research Unit, The Royal Melbourne Hospital, Parkville, Victoria, Australia Regulatory T cells (Tregs) suppress pro-inflammatory immune responses and prevent autoimmune disease. Many types of Tregs have been described, the prototypic in mice defined as CD4 þ CD25 þ with high expression of the Foxp3 transcription factor. However, Fox P3 is not a reliable marker of human CD4 þ CD25 þ Tregs and Tregs activated by disease-associated antigens have not been well characterised. By comparing autoantigen-activated CD4 þ Tcell clones, we identified CD52 as a marker of suppressor clones. We then showed that high expression of CD52 on antigen-activated T cells identified a unique Treg population in human blood. CD52hi Tregs were not distinguished by markers of CD4 þ CD25 þ Tregs and did not require cell contact for suppressor function. Following activation by