Responses to alloantigens and transplant rejection CH15 Responses to alloantigens and transplant rejection Immune response against grafted cells tissues, or organs Ch16 Immune modulators

The immune system Chapter 15 Transplantation of tissues and organs Third edition Peter Parham (2009) Chapter 15 Transplantation of tissues and organs

Bone marrow transplantation Identity of transplantation antigens Type and prevention of immune response in rejection of solid organs Bone marrow transplantation

Donor

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

Type and prevention 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) Immediate Repeated blood transfusions Repeated pregnancies Previous graft Immediate graft death C’, blood clotting

Hyperacute rejection

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

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

Minor histocompatibility Ag HLA matching Minor histocompatibility Ag Polymorphic Ag (proteins that differ in amino acid sequence between individuals)

Two ways of allo-Ag recognition Donor Donor Recipient

Chronic rejection (months - years) FcR Infiltration Fibrosis Atrophy

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

T cells : thymus MHC restriction Positive selection

MHCa MHCaxb Hematopoiesis MHCb APC MHCa MHCaxb MHCb

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

HLA-haploidentical family members

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

Graft-versus-host disease (GVHD) Recipient DC Stringent T-cell depletion

Activation of allogeneic T cells 膽紅素 Tissue inflammation Acute GVHD: First few months Cytokine storm Graft-versus-leukemia effect Graft-versus-tumor effect Activation of allogeneic T cells