Adaptive Immunity in Organ Transplantation

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Nancy Atkins
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1 Adaptive Immunity in Organ Transplantation Rainer Krebs Transplantation Laboratory Cardiopulmonary Research Group Adaptive vs innate immunity INNATE immunity: first line of defense quick reaction, less sustained reactions never change character no long-lasting or protective immunity initiation and direction of adaptive immune responses 1

first line of defense quick reaction, less sustained reactions never change character

2 Adaptive vs innate immunity ADAPTIVE immunity: more versatile specific memory (vaccination) changes with every experienced infection Definitions DONOR: individual from whom an organ is taken for transplantation RECIPIENT: individual that receives an organ ALLOGRAFT: a tissue graft from a donor genetically unrelated to the recipient 2

individual from whom an organ is taken for transplantation RECIPIENT: individual

3 Definitions AUTOGRAFT: graft stems from host s own tissue SYNGRAFT: donor and recipient are genetically identical ALLOGRAFT: a tissue graft from a donor genetically unrelated to the recipient Adaptive immune system in transplantation Adaptive IS: B cells and T cells B cells: mature in the bursa of Fabricius (in birds) T cells: mature in the thymus 3

to the recipient Adaptive immune system in transplantation Adaptive IS: B cells and T

4 Adaptive immune system in transplantation Sir Peter Medawar treated burns suffered by pilots in the Battle of Britain Adaptive immune system in transplantation skin transplants from unrelated donors were unsuccessful Medawar started studies on skin transplantation in animal models 1944: first description of lymphocytes in skin grafts soon after transplantation 4

from unrelated donors were unsuccessful Medawar started studies on skin transplantation in

5 Adaptive immune system in transplantation a skin graft from a genetically unrelated donor is rejected in 7 10 days by a naïve host = first set reaction a skin graft from the same donor to the same recipient is rejected within 2 3 days = second set reaction a second graft from a donor unrelated to the first donor induces a first set reaction Adaptive immune system in transplantation rejection is donor specific: host-versus-graft response rejection is linked to memory: the response to a second graft from the same donor is enhanced the ability to induce a second set reaction against a graft can be adoptively transferred to a naïve host: transfusion of immunocompetent lymphocytes derived from a recipient of a genetically similar graft 5

transplantation rejection is donor specific: host-versus-graft response rejection is linked to memory: the response to a second graft from the same donor is enhanced the ability to

6 Adaptive immune system in transplantation T lymphocyte = principal mediator of alloimmune response mice devoid of T cells do not reject allografts humans: T cell depletion prevents rejection (until they return to the circulation) What does the immune system recognize in an allograft? 6

allografts humans: T cell depletion prevents rejection (until they

7 Alloantigen recognition allorecognition = discrimination of self- and non-self tissues principal TX antigens: MHC major histocompatibility complex cell surface molecules in humans: HLA (Human Leukocyte Antigen) HLA-matching gives survival advantage Alloantigen recognition mhags: minor histocompatibility antigens any other polymorphic proteins account for rejection of HLA-matched organs so far, more than 50 mhags described 7

Antigen) HLA-matching gives survival advantage Alloantigen recognition mhags: minor histocompatibility

8 Alloantigen recognition Activation of antigenpresenting cells 8

9 T cells activation: by APC in secondary lymphoid organs (lymph nodes, spleen) T cells activation triggers proliferation, differentiation, migration migration into periphery: upon reencounter of their antigen (specific!), effector functions are triggered 9

differentiation, migration migration into periphery: upon

10 T cells two main types of mature T cells: CD4 + T cell: recognize peptides on MHC class II stimulate/downregulate immune responses (helper T cells) CD8 + T cell: recognize peptides on MHC class I kill cells that display foreign antigen T cells after activation, CD4 + and CD8 + T cells develop first into effector and later into memory cells = most effector T cells die (apoptosis), some survive as memory cells good in general, bad for allografts 10

cells that display foreign antigen T cells after activation, CD4 + and CD8 + T cells develop first into effector

11 Antigen recognition any given microbe: about 1 in 1,000,000 T cells would recognize any peptide derived from the microbe % Antigen recognition immune reaction to allograft: 1 to 10 % of all T cells take part 11

12 Immune response to allografts Why do T cells react to allografts? developing T cells are chosen for their ability to recognize MHC (positive selection=> bias) TCRs also recognize non-self MHC = cross-reactivity e.g., CTL specific to EBV are highly alloreactive to certain HLA molecules Immune response to allografts in large part: memory response all humans harbor alloreactive memory T cells (50 % of all alloreactive T cells) alloreactivity is partly shaped by one s immunological memory 12

13 Memory T cells significance for transplantation: refractory to costimulatory blockade cell depletion regulatory-cell-mediated suppression memory cells can be generated in response to: transplantation blood transfusion pregnancy lymphopenia infection Regulatory T cells generated in the thymus as well as in the periphery Tregs limit effector cell damage to healthy tissue Tregs also prevent rejection of transplants 13

transfusion pregnancy lymphopenia infection Regulatory T cells generated in the thymus as well as in the

14 Regulatory T cells exact mechanisms of downregulation unknown several mechanims described: regulation of cytokine production adjusting the expression of costimulatory molecules inhibition of proliferation conversion to a regulatory phenotype induction of anergy Classification of Rejection hyperacute rejection: antibody-mediated acute rejection: cell-mediated antibody-mediated chronic rejection: cell-mediated antibody-mediated 14

conversion to a regulatory phenotype induction of anergy Classification of Rejection hyperacute rejection:

15 Hyperacute Rejection a matter of minutes or hours after TX = immediate allograft dysfunction occurs only in vascularized grafts donor-specific antibodies bind to endothelial cells Hyperacute Rejection eventually leading to microvascular thrombosis => graft necrosis 15

donor-specific antibodies bind to endothelial cells Hyperacute

16 Hyperacute Rejection Prevention: checking ABO-compatibility cross-matching of donor and recipient = excluding presence of antidonor HLA antibodies Causes of Presensitization presensitization => presence of donor-specific antibodies blood transfusions pregnancy previous transplantations infections inflammation 16

Presensitization presensitization => presence of donor-specific antibodies

17 Acute Rejection takes days/weeks/months to develop results from two mechanisms acting alone or in combination: T cell-mediated: acute cellular rejection B-cell-mediated: acute humoral rejection Prevention of Acute Rejection prevention of perioperative injury brain-death < cardiac death < living donor preservaton injury ischemia-reperfusion injury prevention of postoperative injury infections, surgical injury, GERD blood group matching leukocyte cross-matching immunosuppressive drugs 17

of perioperative injury brain-death < cardiac death < living donor preservaton injury ischemia-reperfusion injury

18 Prevention of Acute Rejection deplete lymphocytes prevent lymphocyte activation / responses to activation regulate the traffic of APC and lymphocytes between the allograft and the secondary lymphoid organs Chronic Rejection develops in months / years cell-mediated (DTH) antibody-mediated (DSA) immunological causes non-immunological causes 18

allograft and the secondary lymphoid organs Chronic Rejection develops in months /

19 Chronic Rejection Common manifestations in all organs vasculopathy = diffuse intimal thickening of arteries parenchymal fibrosis low-grade inflammation (chronic) angiogenesis, lymphangiogenesis Chronic Rejection organ-specific manifestations heart: cardiomyopathy / diastolic dysfunction lungs: obliterative bronchiolitis kidney: tubular atrophy, glomerular sclerosis liver: vanishing bile ducts 19

Chronic Rejection organ-specific manifestations heart: cardiomyopathy / diastolic dysfunction

20 Tolerance the holy grail of organ transplantation a state of donor-specific unresponsiveness without the need for ongoing pharmacologic immunosuppression rare cases have been reported Tolerance immune tolerance induction shown in many rodent models small success in humans/primates Why? A.o.: experimental animals live in pathogenfree environments humans are exposed to pathogens generate an immense pool of memory T cells (cross-reacting) 20

shown in many rodent models small success in humans/primates Why? A.o.: experimental animals live in

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins Adaptive Immunity Chapter 17: Adaptive (specific) Immunity Bio 139 Dr. Amy Rogers Host defenses that are specific to a particular infectious agent Can be innate or genetic for humans as a group: most microbes