医学免疫学课件：Cellular and Molecular Mechanisms in Graft-versus-host Disease

1、Cellular and Molecular Mechanisms in Graft-versus-host Disease01 Introduction02 Cells03 Molecules04 Therapy01 IntroductionHSCTHematopoietic stem cell transplantation (HSCT)More than half a century agoRare cases with refractory acute leukemia, combined immune deficiency, or aplastic anemiaStem cell s

2、ource: bone marrow, peripheral blood or cord blood1 Alois Gratwohl, Helen Baldomero, Jakob Passweg: Current Opinion Hematology 2013, 20:485493.The formation of blood cells takes place in bone marrow, and malfunctioning of bone marrow cells can lead to illnesses such as leukemia. From the mid-1950s D

3、onnall Thomas developed methods of providing new bone marrow cells for people through transplants. Using radiation and chemotherapy, the bodys own bone marrow cells are killed and the immune systems rejection mechanism is subdued. Bone marrow cells from a donor are then provided through a blood tran

4、sfusion.More than 60 000 transplants each year 1,000,000th transplant in early 2013Malignant and nonmalignant conditionsGraft-versus-tumor (GVT) effectAutologous HSCTAllogeneic HSCTAggressive hematologic malignanciesNonneoplastic marrow failure syndromes, inborn errors of metabolism, and immunodefic

5、iency syndromesHSCTGVHDGraft-versus-host disease (GVHD)One of the most frequent complications in HSCTThe recognition of host tissues as foreign by immunocompetent donor cells2 Sharon R. Hymes, Amin M. Alousi, Edward W. Cowen: J Am Acad Dermatol 2012;66:515.e1-18.Classification Acute GVHDChronic GVHD

6、HistoricallyTodayLess intense conditioning regimens & greater use of immune-modulating strategiesReclassification National institutes of health (NIH) consensus development projectTable I.Categories of acute and chronic graft-versus-host diseaseCategoryTime of symptoms after HCT or DLIPresence of acu

7、te GVHD featuresPresence of chronic GVHD featuresAcute GVHD Classic100 daysYesNo Persistent, recurrent, or late-onset100 daysYesNoChronic GVHD ClassicNo time limitNoYes Overlap syndromeNo time limitYesYesClassification Acute GVHD Primary clinical featuresSkin rashBilirubin elevationDiarrheaAcute GVH

8、D Table II. Clinical staging of acute graft-versus-host diseaseStageSkinLiverGut0No rash related to GVHDBilirubin, 2 mg/dLNone1Maculopapular rash 25% of body surface area without associated symptomsBilirubin, 2 to 500 to 1000 mL/d nausea and vomiting2Maculopapular rash or erythema with pruritus or o

9、ther associated symptoms covering 25 and 50% of body surface area or localized desquamationBilirubin, 3 to 1000 to 1500 mL/d, nausea and vomiting3Generalized erythroderma or symptomatic macular, papular, or vesicular eruption with bullae or desquamation covering 50% of the bodyBilirubin, 6 to 1500 m

10、L/d, nausea and vomiting4Generalized exfoliative dermatitis, ulcerative dermatitis or bullaeBilirubin, 15 mg/dLSevere abdominal pain with or without ileusChronic GVHD Approximately 60% to 70% of patientsSclerotic manifestationsNonsclerotic manifestationsSkin (75%), oral mucosa, liver, and eyeLess co

11、mmonly, the GI tract, lung, esophagus, female genital tract and joints02 CellsImmune cells implicated in GVHDMacrophagesDendrite cellsT cellsB cellsNK cells3 Lingling Zhang, Jianhong Chu, Jianhua Yu, et al: Journal of Leukocyte Biology Vol.99, No.2 , pp:279-287, February, 2016.MacrophagesConditionin

12、g regimenGut epithelial cells injury activateChemokines Host APCs low-level IL-10High-level IL-1 and TNF-Dendrite cellsPlasmacytoid DCs & myeloid DCsStimulate Th17 responsesInitiate and perpetuate GVHDDonor myeloid DCs migrationDonor DCs MHC-IIAgTCRT cellsDendrite cellsHost CCR7+ DCs Induce donor T

13、cell Express chemokine receptorsRegulate the migration of activated DC from tissue to draining lymph nodeDepletion of CCR7+ host DCs prevention of aGVHDpreservation of GVL effectsDendrite cellsimmunosuppressive cytokines (High expression)Tolerogenic dendritic cells (TDCs) MHC (Low expression) Costim

14、ulatory molecules (Low expression)Expand Foxp3+ TregSuppress allo-CD4 T cell proliferationT cellsTh17 cellsIL-17A, IL-17F, IL-22, and IL-21Donor DCs MHC-IIAgTCRCD4 T cell Th2 cellsproinflammatory cytokinesTh1 cells Treg, Th1, Th2, or Th17 phenotypesT cellsDonor CD8 T cells Kill recipient B cellsDama

15、ge recipient medullary thymic epithelial cells Dual TCR T cellsHost CD8 T cellsDown-regulate donor CD8 T cellsT cellsImbalance between Th17 cells and TregsSignificantly increased Th17:Th1 and Th17:Treg ratios in liver cGVHDaGVHD: Th17 percentage and RORt expression Treg percentage and Foxp3 expressi

16、on Adoptive transfer of Tregs CD8hi Tregs Reducing alloreactive T cell proliferation Decreasing inflammatory cytokine and chemokine secretion B cellscGVHD is characterized by the production of autoantibodiesCognate recognition of foreign MHC II of host B cells by donor alloreactive CD4 T cellsaGVHD:

17、 delayed B cell reconstitution and impaired antibody responsecGVHD: Inadequate reconstitution of naive B cells and high levels of BAFF4 Stefanie Sarantopoulos, Bruce R. Blazar, Corey Cutler, et al: 2015 January ; 21(1): 1623.B cellsDonor B cellsAugmenting the clonal expansion of the residual autorea

18、ctive donor CD4 T cellsAugmenting donor CD4 T differentiation into proinflammatory Th2 cellsBregs Negatively regulate T cell immune responsesSecretion of regulatory cytokines, such as IL-10Direct cellcell contactNK cellsMediate early GVL reactionsAlloreactive, donor-derived NK cellsKill recipient AP

19、Cs and cytotoxic T lymphocytesPrevent GVHD and graft rejectionDefense against cytomegalovirus infection in an early post-transplant period Cells3 sequential phasesActivation of APCsEffector cells activation, proliferation, differentiation, and migrationTarget tissue destruction03 MoleculesCytokinesP

20、roinflammatory cytokines are increased in aGVHDTNF-in all phases of GVHD pathophysiologyTh17-associated cytokines, including IL-6, IL-1 b, IL-17, IL-21, IL-23, and IL-23RRegulatory cytokine suppresses GVHDIL-10Host and donor B cell-derivedSurface moleculesCostimulatory moleculesICOS: activate CD4 an

21、d CD8 T cellsSOCS: Th1 cell activationCD moleculesCD26, CD83, CD132PRRsThe complement systemC3Signaling moleculesThe PD-1 pathway suppress cGVHDNotch pathway of cellcell communicationProtein kinasesTranscription factorsc-Rel04 TherapyCurrent prevention strategiesLimiting organ toxicity by reducing i

22、ntensity of chemotherapy conditioningPharmacological AgentsInhibition of allo-reactive T cellsMethotrexate (MTX), calcineurin Inhibitors, corticosteroids, cyclophosphamide, Mycophenolate Mofetil (MMF), SirolimusDepletion of T lymphocytes5 Nancy Y. Villa, Masmudur M. Rahman, Grant McFadden, et al: Vi

23、ruses 2016, 8, 85. Current treatmentNo specific FDA-approved treatmentFirst-line therapy: corticosteroids like prednisoneSuppress the immune response by inhibiting the production of inflammatory cytokinesToxicities and limited responsesCorticosteroid-refractory GVHD (SR-GVHD): only 530% long-term su

24、rvivalCurrent treatmentOther agents: horse rabbit anti-thymocyte globulin ATG; daclizumab, antibodies against TNF (e.g., etanercept or infliximab), pentostatin, MMF, and sirolimus.Second line treatment:Anti-metabolites (e.g., MMF or methotrexare), extracorporeal photopheresis or light therapyAlternative and Novel StrategiesB Cell DepletionCellular Suicide Gene TherapyRegulatory T CellsTargeting Co-Stimulatory MoleculesMolecular Targets in T Cells That Modulate Graft-versus-Host ResponsesVirotherapyReference1 Alois Gratwohl, Helen Baldomero, Jakob Passweg: Hematopoietic stem c