Transplantation of Tissues and Organs Chapter 15 Transplantation of Tissues and Organs Immune response against grafted cells, tissues, or organs

Lymphocyte activation Signal 1-3 Lymphocyte activation Innate immunity Effector response

The transplant patient is already inflamed before transplantation Donation program Safety Living healthy donors Donated organ may also be inflamed Ischemia 局部缺血

Donor

Major histocompatibility complex (MHC) Identity of transplantation antigens Major histocompatibility complex (MHC) MHC Ag Class I Class II Autograft Isograft Allograft Xenograft

Identity of transplantation antigens Erythrocyte Ag : ABO, Rh, etc. Blood transfusion Erythrocyte Ag : ABO, Rh, etc. 15.3 A RHD- The most widespread kind of transplantation in clinical medicine

Type of immune response in rejection of solid organs Hyperacute rejection (within 24h) Acute rejection (first few weeks) Chronic rejection (months - years)

Hyperacute rejection Pre-existing Ab e.g. Anti-MHC, A/B/O ABO/MHCI Ag C’, blood clotting Immediate graft death

Source of pre-existing antibody Repeated blood transfusions Repeated pregnancies Previous graft Sensitization Panel reactive antibody (PRA) A representative HLA panel of individuals from the population The higher the PRA value , the more difficult to find a suitable transplant donor 15.5

The prevention of hyperacute rejection Blood typing Cross-matching test 移植前 Serum D Ab

Cell-mediated immunity (CMI) Acute rejection (first few weeks) Cell-mediated immunity (CMI) Th1 response Macrophages (Type IV hypersensitivity) CTLs Cross reactivity MHC polymorphism Allogeneic T cells The frequency of T cells specific for any non-self MHC molecules is relatively high

Affinity Cross reactivity High frequency of allogeneic T cells Self Cross reactivity High affinity to non-self MHC Ag

Acute rejection Anti-CD3 Donor DC 15.9

In vitro mixed lymphocyte reaction (MLR) 15.10 T: recipient APC: donor

The prevention of acute rejection Tissue typing of HLA-I/II Blood typing Tissue typing of HLA-I/II Serological typing DNA analysis Immunosuppressive agents

15.14

Immunosuppressive agents Steroids 15.17

15.18

Killing of proliferating cells Immunosuppressive agents Cytotoxic drugs Killing of proliferating cells Pro-drug 15.25 Side effect: liver, kidney, etc

Inhibition of T-cell activation Immunosuppressive agents Cyclosporin A (CsA) Tacrolimus (FK506) Inhibition of T-cell activation 15.19 Anti-T antibody

mTOR: mammalian target of rapamycin Activated by associated proteins Reduce T-cell proliferation G1 phase arrest Promote apoptosis Increase Treg number Kinase Activated by associated proteins

Increase the risk of cancer and infection Immunosuppressive agents Increase the risk of cancer and infection

Chronic rejection (months - years) FcR Antibody against HLA-I: Infiltration of CD40 B cells and CD40L TH cells

Chronic rejection (months - years) Antibody against HLA-I: Infiltration of CD40 B cells and CD40L TH cells Fig. 15.13

Major type of Ag presentation in transplantation rejection Chronic rejection Dead cells Acute rejection 15.12

Minor histocompatibility Ag HLA matching Minor histocompatibility Ag Male Ag 15.40

Transplantation that not requiring tissue typing of HLA-I/II No immunosuppressive therapy 15.29 Liver

Bone marrow transplantation Genetic diseases of blood cells Cancer therapy Intravenous infusion Chemotherapy Repopulation Reconstitution of the patient’s immune system and also their red cells and platelets

Genetic diseases of blood cells 15.32

15.34

移植相容性 Genetics of MHC 遺傳

移植 相容性 Transplantation

HLA-haploidentical family members

T cells : thymus MHC restriction Positive selection

MHCa MHCaxb Hematopoiesis MHCb APC MHCa MHCaxb MHCb

Thymic non-lymphoid stroma: MHC restriction Bone marrow-derived APC Bone marrow chimera Blood type Thymic non-lymphoid stroma: MHC restriction Bone marrow-derived APC The more HLA allotypes they share, the better it works

Colonization of HSC in the bone of recipient Engraftment: Colonization of HSC in the bone of recipient Myeloablative therapy Enrichment Niche Fig. 1.13

Stringent T-cell depletion 15.35 Stringent T-cell depletion

Activation of allogeneic T cells 膽紅素 15.36 Tissue inflammation Cytokine storm Acute GVHD: First few months Activation of allogeneic T cells

Graft-versus-leukemia effect Graft-versus-tumor effect

graft-specific tolerance Hematopoietic cell transplantation can induce tolerance to solid organ transplants Induction of graft-specific tolerance 15.44

A non-immunogenic tissue barrier An immune privileged site Fetus Natural allograft A non-immunogenic tissue barrier An immune privileged site