免疫學(xué)與免疫系統(tǒng)疾?。旱?7章 Tumor and Transplatation Immunology

1、Xiao-Ping Chen 2015Tumor and Transplantation ImmunologyXiao-Ping Chen 2015Anti-tumor immunity (immune surveillance) does exist, but not be as effective as anti-infection immunity.Fig10-1 p190Xiao-Ping Chen 2015Because tumor antigens are weak and not specific.Xiao-Ping Chen 2015Phenomenon of tumor re

2、jection suggests the existence of tumor cell-specific antigens, but only in limited situations.Some tumor cells can induce tumor antigen-specific immune response with memory.Xiao-Ping Chen 2015Tumor-specific antigens (TSA) and tumor associated antigens (TAA) Oncofetal Antigens (CEA, CA-125)TSA=tumor

3、 specific antigensTAA=tumor associated antigensFig10-2 p191Xiao-Ping Chen 2015Virus-associated TSA are oncogenic.Xiao-Ping Chen 2015The transformation molecules (TSA) from EBV are LMP1, LMP2A and EBNA. Their oncogenic potentials varies depending on immune status of the hosts. ImmunecompromisedImmune

4、competentXiao-Ping Chen 2015TAA are extremely useful for the screening and diagnosis of tumor.Xiao-Ping Chen 2015CTL is the primary immunity. Cross-priming and cross-presentation is the major pathway to generate effector CTL to fight against tumor cells. Cross-presentation denotes the ability of DCs

5、 to take up, process and present extracellular antigens with MHC class I molecules to nave CD8+ T cells and activate them into cytotoxic T cells. This process is necessary for immunity against most tumors and against viruses that do not readily infect DCs. Fig10-3 p192Xiao-Ping Chen 2015The second s

6、ignals may be stimulated by the tumor-associated DAMPUnlike microbial pathogens, tumor cells do not express specific PAMP.However, when tumor cells grow to certain volume, cell death (necrosis) occurs. This will result in endogenous PAMP or danger signals (DAMP) or alarmins to be released.HMGB1 (The

7、 chromatin-associated protein high-mobility group box 1)-RACE-NF-B activationDNA-TLR9- NF-B activationPurine metabolites (ATP, adenosine and uric acid)-inflammasome activation-IL-1 Xiao-Ping Chen 2015Evasion of immunity by tumors1. TGF-2. PD-1 (on T), PD-L1 or PD-L2(on tumor).Fig10-4 p192Xiao-Ping C

8、hen 2015Immunological approaches for cancer therapyXiao-Ping Chen 2015Antibody-mediated (targeting) treatment2 strategies:1. Used for targeting: fused with cytotoxic agents (toxins, radionuclides, chemotherapeutic drugs) Toxins: ricin (stops protein synthesis), calicheamicin (DNA breaks)Radionuclide

9、s: 90Y = yttrium;111I = indium2. Antibody itself initiates apoptosis, like anti-CD20 in the treatment of Non-Hodgkins B-cell lymphoma (CD20 is not expressed on stem cell, anti-CD20 wont cause leukopenia).Xiao-Ping Chen 2015Tumor vaccineDC vaccineDNA vaccineFig10-5 p195Xiao-Ping Chen 2015Viral protei

10、ns as vaccines to prevent cancers caused by virus: HPV16/18 as cervical cancer vaccine+HPV16 VLPsHPV 18 VLPsAntigensAS04 adjuvant+Aluminium salt(Al(OH)3)MPLimmunostimulantVLP = Virus-like particle; MPL = monophosphoryl lipid A.AS04-containing vaccineXiao-Ping Chen 2015The period between HPV infectio

11、n and occurrence of cervical cancer can be very long, thus HPV vaccines are preventively given to preteens before reaching sexually active age.1. CDC recommends that all 11 or 12 year old girls get the 3 doses (shots) of HPV vaccine to protect against cervical cancer, for girls and young women ages

12、13 through 26 should get HPV vaccine if they have not received any or all doses when they were younger. 2. All boys aged 11 or 12 years, and for males aged 13 through 21 years, who did not get any or all of the three recommended doses when they were younger. Xiao-Ping Chen 2015Immunity developed tow

13、ards tumors is usually not strong enough to stop tumor from growing.Reasons can be because tumor cells are self proteins, and no PAMP expressed like those in microbes.Other reason include that tumor cells are evolved to escape immune surveillance via various pathways.Some tumor specific antigens are

14、 identified, they are derived from altered or aberrant expression of self proteins, oncogene products, virus product and etc.Effective anti-tumor immunity relies on CTL, which are activated in the tumor-bearing host via cross-priming and cross-activation. Tumor vaccines are built on identification o

15、f tumor specific antigen and effective adjuvants.SummaryXiao-Ping Chen 2015Questions1.What are the types of tumor antigens that the immune system reacts against? What is the evidence that tumor rejection is an immunologic phenomenon?2.How do CD8+ T cells recognize tumor antigens, and how are these c

16、ells activated to differentiate into effector CTLs?3.What are some of the mechanisms by which tumors may evade the immune response?4.What are some of strategies for enhancing host immune responses to tumor antigens?Xiao-Ping Chen 2015Transplantation rejection is a result of adaptive immune response

17、towards alloantigens.Adaptive immune responseForeign AgSelf AgAllo AgImmunityAutoimmunityTransplant rejectionUpregulationClearance of AgsToleranceXiao-Ping Chen 2015no rejectionrejectionTypes of translplant -AgXiao-Ping Chen 2015Types of translplant -AgAntigen Source Kind of graft Auto Ag Self Autog

18、raft Syngeneic Ag Genetically Syngeneic graft (isograft) identical Allogeneic Ag Unrelated Allogeneic graft same species Xenogeneic Ag Different species Xenogeneic graft Xiao-Ping Chen 2015Allograft RejectionXiao-Ping Chen 2015Types of allograftSolid organs-graft-allogeneic graft rejection (recipien

19、t towards donor)Bone marrow-stem cell GVHR (donor towards recipient)Blood transfusion-Blood Ags-transfusion reactionSpecial allograft: fetuswell toleratedXiao-Ping Chen 2015The graft rejection is caused by MHC disparityXiao-Ping Chen 2015Especially MHC class II antigensXiao-Ping Chen 2015Matching th

20、e donor and recipient at the MHC locus improves the outcome, but not completely. In kidney transplant, matching HLA-A, B and DR (linked with DQ) is important for the graft survival.Xiao-Ping Chen 2015Minor H(histocompatibility) antigens also contribute to the allograft rejection. Eichwald EJ and Sil

21、mser CR Transplant Bull 2:148, 1955Xiao-Ping Chen 2015Minor H antigens elicit slower rejecting response. Xiao-Ping Chen 2015Els Goulmy Human Immunol 67:433, 2006Identified minor H antigens in humanMost of them are MHC I restricted.Xiao-Ping Chen 2015T-cell mediated1. Graft rejection does not occur o

22、n nude mice (T-cell deficiency).2. Adoptively transferred T cells can restore graft rejection in nude mice.3. Removal of T cells can prolong the graft survival.Xiao-Ping Chen 2015Why and how do MHC molecules mount effective rejection immune responses? Xiao-Ping Chen 2015The frequency of nonself MHC

23、reactive (alloreactive) T cells is much higher than that of non MHC-reactive T cells.1-10% of T cells are nonself MHC-self peptide reactive, much higher than the 1/104-106 towards foreign peptide-self MHC.Why?Xiao-Ping Chen 2015The cross-reaction occurred between allogeneic (donor) MHC-donor peptide

24、 and self (recipient) MHC-recipient peptide may contribute to the high frequency.Fig10-7 p198Less than 0.1% of MHC(105) on the cells presenting foreign peptide99.9% of those are bound with self-peptide. Since no foreign peptide needed for allogeneic stimulation by allogeneic MHC, thus the frequency

25、and chance is much higher.Xiao-Ping Chen 2015Allogeniec MHC molecules can activate recipient T cells via direct or indirect presentation pathwayFig10-8 p199Induced alloreactive CTL can target to donor cells directlyacute rejection.Induced alloreactive CTL can not kill donor cells directly. More like

26、ly induced Th and APC from the recipient exerts its rejection effects similar to that in DTH(chronic rejection) in the graft.Donor DCRecipient, self MHC-restrictedRecipient T, allo MHC-restrictedReceipient DCCross-presentation of allogenenic MHCXiao-Ping Chen 2015The alloreactive T cell is measured

27、by mixed leukocyte reaction (MLR)Organ recipientOrgan donorThe level of T cells proliferation reflect the level of MHC mismatch between donor and recipient.Xiao-Ping Chen 2015Effector mechanisms of allograft rejectionAb IgM-mediated, minutes to hoursT cells and Ab-mediated, days to weeksInterstitium

28、 damageArtery damageTh mediated DTH, months to yearsSmooth muscle cell proliferationarteriosclerosisFig10-9 p201Xiao-Ping Chen 2015Bone marrow transplantation and graft versus host rejection (GVHR)Xiao-Ping Chen 2015When to use1. To treat blood malignancy, like leukemia.2. To supply good seed after

29、chemo or radiation therapy.Problems1. Allogeneic stem cells from the donor are extremely easy to be rejected by alloreactive T and NK from the recipient. HLA matching is more important in bone marrow transplantation than in solid organ transplantation.2. GVHR: alloresponse mediated by alloreactive T

30、 cells from donor towards recipients.3. ImmunodeficiencyXiao-Ping Chen 2015GVHR Mechanistically, it is the reverse of graft rejection, but it is severer if MHC is mismatched. Thus matching HLA is required for bone marrow transplantation. The alloreactive T cells from donor bone marrow can also be ac

31、tivated either via direct pathway or indirect pathway.Two A markers, two B markers, two C markers, and two DRB1 markers. Some doctors look for an additional marker, called DQ, to match. An adult donor must match at least 6 of these 8 HLA markers. Many transplant centers require at least a 7 of 8 mat

32、ch.Xiao-Ping Chen 2015The symptoms of GVHR is widespread including multiple organs and tissues. It mainly causes epithelial cell death.Skin manifestationXiao-Ping Chen 2015Prevention and treatment of allograft rejectionXiao-Ping Chen 2015Approach I: Matching1. ABO typing: natural Ab (IgM) will cause

33、 hyperacute rejection in all kinds of grafting.2. Tissue typing: (commonly HLA-A,B, C and DR)Serologic typing: Known anti-HLA Ab+ leukocytes+complementor by ELISACellular typing: MLR Molecular HLA typing: PCR and sequencing of polymorphic region. 3. Screening for the presence of preformed antibodies

34、: Cross-matching: recipients serum + cells from potential donors + complementXiao-Ping Chen 2015Approach II: Immunosuppression agentsFig10-10 p202Consequences: susceptible to infections; cancerXiao-Ping Chen 2015The T cell inhibitory agent cyclosporin improves the graft survival greatly.Xiao-Ping Ch

35、en 2015But the side effects of immunosuppressants are serious and long-term.Weiss et alXiao-Ping Chen 2015Approach III: Induce donor-specific central tolerance1. Creating mixed lymphohematopoietic chimerism in the recipient.Peter MedwarXiao-Ping Chen 20151. Creating mixed lymphohematopoietic chimeri

36、sm in the recipient.The recipient is irradiated to kill alloreactive T and make “room” for donor stem cells transferred.Approach III: Induce donor-specific central toleranceXiao-Ping Chen 2015Approach III: Induce donor-specific central toleranceWeiss et althymo-heart2. Creating mixed thymic chimeris

37、m in the recipient.Many technical challenges. Use composite organs like thymo kidney or thymo-heart as donor entity. Use BM transplantation together with bones.Xiao-Ping Chen 2015Approach IV: Induce donor-specific peripheral tolerance1. Block of co-stimulation molecules using CTLA-4-Ig, anti-B7, ant

38、i-CD40L.CTLA4-IgInhibits T cell activation by blocking B7 costimulator binding to T cell CD28; used to induce tolerance (experimental)Anti-CD40 ligandInhibits macrophage and endothelial activation by blocking T cell CD40 ligand binding to Macrophage CD40(experimental). Induce T cell apoptosisXiao-Pi

39、ng Chen 2015XenograftXiao-Ping Chen 2015Paucity of organ source is a critical problem in this field.Xiao-Ping Chen 2015Limited success has been achieved.Xiao-Ping Chen 2015Swine (pig) seems to be a better organ source.Xiao-Ping Chen 2015Hyperacute rejection is the major problem for xenograft.Xiao-Pi

40、ng Chen 2015AbstractHuman anti-pig antibodies were obtained by perfusing pig hearts (n = 4) and kidneys (n = 8) with human AB or O plasma followed by elution with 3 M NaSCN. The antibodies were screened against a panel of 132 synthetic carbohydrates conjugated to bovine serum albumin using an enzyme

41、-linked immunoassay. An anti-immunoglobulin antibody was also used to detect immunoglobulin deposits on pig tissues. Four carbohydrate molecules with a terminal -galactose residue bound all but one of the human anti-pig kidney antibodies and most of the anti-pig heart antibodies. These were: (i) Gal

42、(13)Gal(14)GlcNac (linear B type 2); (ii)Gal(13)Gal(14)Glc (linear B type 6); (iii) Gal(13)Gal(B disaccharide); and (iv) Gal(-D-galactose). Immunoglobulin deposition was documented post-plasma perfusion in all pig hearts and particularly strongly in all pig kidneys. These results suggest that human

43、anti-pig antibodies are mainly directed against -galactosyl structures. Extracorporeal immunoadsorption of human plasma through columns of the specific synthetic carbohydrate(s) might lead to depletion of anti-pig antibodies and allow discordant xenografting in man. Alternatively, the infusion of th

44、e specific carbohydrate(s) for a period of several days might result in neutralization of the anti-pig antibodies and allow accommodation to take place. Because the presence of anti-pig Gala1-3Gal(aGal) natural antibodies in human.D. K. C. Cooper, A. H. Good, E. Koren, R. Oriol, A. J. Malcolm, R. M.

45、 Ippolito, F. A. Neethling, Y. Ye, E. Romano and N. Zuhdi Transplant Immunol 1:198-205, 1993 Xiao-Ping Chen 2015Pig complement regulatory proteins do not possess regulatory activities towards human complement system.Xiao-Ping Chen 2015Pigs engineered to express human complement regulatory proteins l

46、ike huDAF and CD59 are made. When the organs from engineered pigs were used, limited success has been achieved.Xiao-Ping Chen 2015Some success has been achieved when a1,3-galactose transferase is knocked out (GalT-KO)The knock-out pig was successfully generated in 2002 by 2 different groups. Xiao-Ping Chen 2015Other problems with xenograftInfectious disease caused by zoonostic pathogens1.PERV: Porcine endogenous retrovirus2.PEMV: Porcine encephalomyocarditis