Pathology Course Immunology 1 Ann Sturdy

Transcription

1 Pathology Course Immunology 1 Ann Sturdy Kindly sponsored by:

2 Plan Transplant Immune- Based Therapies Vaccina:on and Memory HIV

3 Transplant (Page 102)

4 Immunology of Transplant Transplant rejec5on is the immune system ac5ng as it should Self versus Non- Self 3 stages of immune response: 1) Recogni:on 2) Ac:va:on 3) Effector Func:on Immune Cell

5 Recogni5on In transplant rejec5on, the immune system recognises: 1) Blood group Ags (ABO) 2) MHCs: Type 1 = A,B,C Type 2 = DP,DQ,DR 3) Minor MHCs In transplant, most important are A, B and DR

6 Recogni5on T- Cells recognize an5gen with MHCs B- Cells can recognise just an5gen An:gen Presen:ng Cells (APCs) present an:gen to TCs (Dendri:c Cells, Macrophages, BCs) In transplant, T- Cells recognise an:gen in 2 ways: 1) Direct 2) Indirect

7 Indirect R APC R TC Recipient APCs present to recipient TCs The immune system working as it should Direct Donor APCs to Recipient TCs D APC R TC

8 Effector Func5on Types of Rejec5on: 1) Hyperacute 2) Acute Cellular 3) Acute An:body Mediated 4) Chronic 5) GvHD

9 1) Hyperacute Very rapid (mins hrs) Due to Pre- formed Ab Ab binds to the endothelium Complement ac:vated Thrombosis/necrosis etc Treatment: Preven:on

10 2) Acute Cellular CD4 Recognises HLA Type IV Hypersensi:vity Reac:on Ac:va:on of CD8, Macrophages, Neutrophils etc CD8 N M On Biopsy see a cellular infiltrate. Treatment: Immunosuppression (T- Cell specific)

11 3) Acute An5body Mediated BC Recognises HLA Ab binds to the endothelium Complement ac:vated Vasculi:s C4d (a complement breakdown product) = a marker Treatment: Remove Ab/Immunosuppression (B- Cell specific)

12 4) Chronic Long Term: Several months to years CD4 M N CD8 AND Non- immune Factors Treatment: Prevent by minimising organ damage

13 GraU versus Host Disease 5) GvHD A phenomenon in Stem Cell Transplant TC Donor immune cells aaacking the recipient (because donor immune system so poor) Basically rejec:on reversed Mainly affects gut, liver and skin Treatment: HLA matching, immunosuppression

14 Matching Donor/Recipient matching has several stages: 1) Donor and recipient blood group and HLA type via PCR 2) Recipient pre- formed Ab via CDC, FACS and Luminex 3) Crossmatch via CDC and FACS HLA Matching? Stem Cell and Kidney YES Heart, Lung, Liver - NO

15 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above For each ques:on which op:on is the MOST IMPORTANT effector?

16 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above 1) 45yr male 2 weeks post renal transplant presents with fever and a rise in crea:nine. Renal biopsy stains posi:ve for C4d

17 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above 2) 45yr male 2 weeks post renal transplant presents with fever and a rise in crea:nine. Renal biopsy shows a cellular infiltrate.

18 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above 3) 32yr female 3 days post bone marrow transplant for aplas:c anaemia becomes jaundiced with diarrhoea and a painful rash

19 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above 4) 42yr male hopes to donate a kidney to his sister, who is in renal failure due to PCKD. On crossmatch, a posi:ve CDC prevents this.

20 EMQ 1 A) Host An:body B) Eosinophil C) TNFa D) Host T Cell E) Donor T Cell F) Donor An:body G) Basophil H) None of the above 5) 48yr male presents 3 years ager a successful renal transplant with fa:gue and a progressive rise in crea:nine.

21 Immune- based Therapies (Page 103)

22 Types of Therapy Suppress it Transplant/Auto- immunity Boost it Infec:on/Malignancy Deviate it Allergy

23 Suppression TC atc atc atc Effector Func5on atc Stops TC ac5va5on OKT3 An:- CD3 Abatacept CTLA4- Ig Cyclosporin/Tacrolimus (block signalling pathways) Stops TC Prolifera5on Basiliximab An:- IL2R Cor:costeriods An:- prolifera:ve Agents Sirolimus (blocks signalling) Stops Effector Func5on Cor:costeroids An:- cytokine Agents BC Specific to B- Cells/Abs Rituximab (An:- CD20) Plasmapheresis Table of agents p104

24 Boos5ng Vaccina5on: later Replacement: HNIG for primary and secondary Ab deficiences Augmenta5on: IFNα: Hep B/C, CML/MM IFNβ: MS IFNγ: Chronic Granulomatous Disease

25 Devia5on Allergen Desensi5sa5on Good for bee/wasp venom, also grass pollen BUT: takes a long :me, risk anaphalaxis Mechanism? Unsure Change in Ab isotype? Change in T REGS? Switch in cytokine balance?

26 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab Choose the single best answer for each of the following descrip5ons

27 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab 1) Suppresses B cells more than T cells

28 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab 2) Suppresses only B Cells

29 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab 3) Used to treat Hepa::s C pa:ents

30 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab 4) An:body to TNFa used in rheumatoid arthri:s

31 EMQ 2 A) Cyclophosphamide B) Rituximab C) IFNg D) Cor:costeroids E) Plasmapheresis F) Mycophenolate Mofe:l G) Etanercept H) Azathioprine I) IFNa J) Infliximab 5) Gene:c tes:ng is carried out before use

32 Vaccina5on (Page 105)

33 The Immunology Vaccina5on relies on MEMORY Both T- Cells and B- Cells are important for a good vaccine

34 Memory B- Cell Long- lived plasma cells Memory cells that differen:ate to plasma cells These cells produce: More Ab, quicker More IgG Higher affinity Ab Generally all round beaer Ab

35 T- Cell (CD4 and CD8) 2 types of memory cell: 1) Central Memory (T CM ) Home to LNs. Very long- lived and can proliferate to effectors CCR7 + CD62L + - allow entry via HEV to LNs Produce IL2 (to support other cells) but no IFN or perforin as not an effector cell 2) Effector Memory (T EM ) Home to :ssue. Rapid effector func:on CCR7 - CD62L - - don t enter LNs Produce IFN and perforin as direct effectors

36 Vaccina5on Defini5on: a biological substance which can be used to illicit an immune response in a host to provide subsequent protec:on Ac5ve: The individual mounts an immune response themselves Passive: Elements of the immune response borrowed from elsewhere

37 Types of Vaccine Table of different types of Ac5ve Vaccine in the notes (page 107) Passive: giving Ig HNIG (Human Normal Ig) Hep A and Measles HBIG Hep B HRIG Rabies Palivizumab - RSV

38 Live v Inac5vated Live: Ogen lifelong protec:on Ac:vates TC and BC to wide range Ag But Virulence? in immune- deficient or reversal Storage IMPORTANT In immunocompromised cau:on with LIVE vaccines HIV Posi5ve pa5ents CAN have MMR, but NO BCG or Yellow Fever Inac5vated: Safe for all Easy storage and cheap But Poor immunogenicity needs boosts+/- adjuvant

39 Adjuvants increase the immune response without altering its specificity Alum: Commonly used.?slow release Ag?primes BCs via IL4 produc:on to give more Ab Freuds Adjuvant: oil emulsion with bits of mycobact cell wall. Used in animals only CpG DNA: Unmethylated only usually found in bacteria so ac:vates IR via TLR9 ISCOMS: Experimental Mul:meric Ag with adjuvant built in.

40 Vaccina5on Schedule Childhood Vaccina5ons 2mth DTaP/IPV/HIB PCV 3mth DTaP/IPV/HIB Men C 4mth DTaP/IPV/HIB PCV Men C 12-13mth Hib/Men C PCV MMR 3yr 4mth DTaP/IPV MMR 13-18yrs Td/IPV BCG (TB): At risk infants vaccinated Girls 12-13yrs HPV At Risk Groups: Anthrax, Hep A, Hep B, Men ACWY, Rabies, Varicella (if not immune) Travel: Cholera, Hep A, Hep B, Jap Enceph, Tick- Bourne Enceph, Typhoid, Yellow Fever

41 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV Choose the most appropriate vaccine for each ques:on

42 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV 1) Given in the UK vaccina:on schedule at 2mths with DTaP/IPV/HIB

43 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV 2) Should not be given to HIV posi:ve children in the UK

44 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV 3) Only a passive vaccine is available

45 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV 4) Recombinant protein vaccine

46 EMQ 3 A) Rabies B) Varicella C) Hep B D) MMR E) PCV F) Meningi:s C G) BCG H) RSV 5) Live vaccine part of rou:ne vaccina:on schedule in the USA but rarely used in the UK

47 HIV (Page 108)

48 HIV on the IS HIV GP120 Ini:al Binding GP41 Conforma:onal Change CD4 - Receptor Destroys CD4 so impairs whole IR CCR5/CXCR4 Co- receptor Impairs APCs Mangles LNs Immune Cell CD4 CD4 DC LN Genital Mucosa Macro Transport

49 IS on HIV Macro/ NK Cell Innate Non- specific Macro/NK cell response TC T- Cell CD4 - HIV specific response to GAG CD8 HIV specific response to ENV An:viral Cytokines: MIP- 1α, MIP- 1β, RANTES HIV BC B- Cell NEUTRALISING Abs to gp120 and gp41

50 HIV is clever BUT HIV 1) Destroys CD4 Cells so lose support for CD8 and BCs too 2) Impairs APCs (Macros and DCs) so Ag isn t presented as well 3) Viral Envelope is very difficult to form a good Ab response against 4) Quasispecies main varia:ons of the virus created due to error- prone RT

51 HIV Progression HIV Macro/ NK Cell TC BC Typical: 8 10yrs Rapid: <3yrs Long- Term Non- Progressors: >10yrs WHY? Quality of the immune response Gene:cs: CCR5Δ32, HLA B27

52 Diagnosis Screening Test: Detects Ab via ELISA Confirma5on Test: Detects Ab via Western Blot Need to have SEROCONVERTED (i.e. started to produce Ab) This gives a 3mth WINDOW PERIOD AUer Diagnosis: Viral Load via PCR CD4 Count via FACS Resistance Tes:ng

53 Treatment Types of HAART Aaachment/Fusion Inhibitors Nucleos(/t)ide/Non- nucleoside RT Inhibitors Integrase Inhibitors Protease Inhibitors

54 Treatment Class Aeachment Inhibitor Fusion Inhibitor Maraviroc Enfuvir:de Group Adverse Effects Injectable Only Specific Adverse Effects Integrase Inhibitor Raltegravir Elvitegravir??

55 Class NRTI (Nucloside) NRTI (Nuclo5de) AZT Treatment Didanosine Group Adverse Effects Mitochondrial Toxicity Stavudine Lamivudine Lipoatrophy Abacavir Tenofovir Emtricitabine Specific Adverse Effects BM Supression(AZT), Pancrea::s (Did) Peripheral Neuropathy (Sta) Hypersensi:vity Reac:on - related to HLA B5701 (Aba) Renal Toxicity (Ten) NNRTI Nevirapine Delavirdine Rash, Hepa::s (Niv) Efavirenz Psychosis (Ef)

56 Treatment Class Protease Inhibitor Group Adverse Effects Indinavir Nelfinavir Metabolic Issues Ritonavir Fosamprenavir Lopinavir Saquinavir CP450 Interac:ons Specific Adverse Effects Typical Regimen: 2NRTIs + PI (or NNRTI) Star5ng Treatment: (BHIVA Guidelines) If CD4 <200 Symptoma:c Start thinking about it when CD4 <350

57 Questions? And Good Luck Kindly sponsored by: