Seminar onSeminar on

Transplantation Immunology: Transplantation Immunology: Organ and Tissue Organ and Tissue Transplantation Transplantation

Immunosuppressive Agents, Immunosuppressive Agents, Immunosuppressive Therapy.Immunosuppressive Therapy.

ByBy

Mr.Pratap J. PatleMr.Pratap J. Patle

Deptt. Of ZoologyDeptt. Of Zoology

R.T.M. Nagpur University, NagpurR.T.M. Nagpur University, Nagpur

ContentsContents IntroductionIntroduction

Immunology of Transplant RejectionImmunology of Transplant Rejection

Tissue and Organ TransplantationTissue and Organ Transplantation

Immunosuppressive AgentsImmunosuppressive Agents

Immunosuppressive TherapyImmunosuppressive Therapy

ConclusionConclusion ReferencesReferences

IntroductionIntroduction

Transplantation immunology - sequence of Transplantation immunology - sequence of events that occurs after an allograft or events that occurs after an allograft or xenograft is removed from donor and then xenograft is removed from donor and then transplanted into a recipient.transplanted into a recipient.

A major limitation to the success of A major limitation to the success of transplantation is the immune response of transplantation is the immune response of the recipient to the donor tissue. the recipient to the donor tissue.

Types of Transplant

Autograft is self-tissue transferred from one body site to another in the same individual.

Isograft is tissue transferred between genetically identical individuals.

Allograft is tissue transferred between genetically different members of the same species.

Xenograft is tissue transferred between different species

Immunology of Immunology of Transplant RejectionTransplant Rejection

Components of the Immune system involved in graft Components of the Immune system involved in graft Rejection :Rejection :1) 1) Antigen presenting cells Antigen presenting cells – –

Dendritic cellsDendritic cells MacrophagesMacrophages Activated B CellsActivated B Cells

2) 2) B cells and antibodies B cells and antibodies – – Preformed antibodiesPreformed antibodies Natural antibodiesNatural antibodies Preformed antibodies from prior sensatizationPreformed antibodies from prior sensatization Induced antibodiesInduced antibodies

3) 3) T cellsT cells

4) 4) Other cells Other cells – – Natural killer cellsNatural killer cells T cells that express NK cell – associated MarkersT cells that express NK cell – associated Markers Monocytes/MacrophagesMonocytes/Macrophages

The Immunology of The Immunology of Allogeneic TransplantationAllogeneic Transplantation

Recognition of transplanted cells that Recognition of transplanted cells that are self or foreign is determined by are self or foreign is determined by polymorphic genes (MHC) that are polymorphic genes (MHC) that are inherited from both parents and are inherited from both parents and are expressed co-dominantly. expressed co-dominantly.

Alloantigens elicit both cell-mediated Alloantigens elicit both cell-mediated and humoral immune responses. and humoral immune responses.

Recognition of Recognition of AlloantigensAlloantigens

Direct PresentationDirect Presentation Recognition of an intact MHC molecule displayed by Recognition of an intact MHC molecule displayed by

donor APC in the graftdonor APC in the graft Basically, self MHC molecule recognizes the structure Basically, self MHC molecule recognizes the structure

of an intact allogeneic MHC moleculeof an intact allogeneic MHC molecule Involves both CD8Involves both CD8++ and CD4 and CD4++ T cells. T cells.

Indirect Presentation Donor MHC is processed and presented by

recipient APC

Basically, donor MHC molecule is handled like

any other foreign antigen

Involve only CD4+ T cells.

Antigen presentation by class II MHC

molecules.

Activation of Alloreactive T Activation of Alloreactive T cells and Rejection of cells and Rejection of

AllograftsAllografts Donor APCs migrate to regional Donor APCs migrate to regional

lymph nodes and are recognized by lymph nodes and are recognized by the recipient’s Tthe recipient’s THH cells. cells.

Alloreactive TAlloreactive THH cells in the recipient cells in the recipient induce generation of Tinduce generation of TDTHDTH cell and cell and CTLs then migrate into the graft and CTLs then migrate into the graft and cause graft rejection.cause graft rejection.

Activation of Alloreactive T cells and Rejection of

Allografts( )SENSATIZATION

Passenger leukocyte

.Class II MHCantigen

2IL HT HT

HTHT

Donar kidney

CTLDTHTCTL

DTHT

LYMPH NODEEFFECTOR

Role of CD4Role of CD4++ and CD8 and CD8+ + T T CellsCells

CD4CD4++ differentiate into cytokine differentiate into cytokine producing effector cellsproducing effector cells Damage graft by reactions similar to Damage graft by reactions similar to

DTHDTH CD8CD8++ cells activated by direct cells activated by direct

pathway kill nucleated cells in the pathway kill nucleated cells in the graftgraft

CD8CD8++ cells activated by the indirect cells activated by the indirect pathway are self MHC-restrictedpathway are self MHC-restricted

Role of Cytokines in Role of Cytokines in Graft RejectionGraft Rejection

IL – 2IL – 2, , IFN – IFN – , and TNF - , and TNF - are important mediators of are important mediators of graft rejection.graft rejection.

IL – αIL – α promotes T-cell proliferation and generation of T – promotes T-cell proliferation and generation of T – Lymphocytes.Lymphocytes.

IFN - IFN - is central to the development of DTH response.is central to the development of DTH response. TNF - TNF - has direct cytotoxic effect on the cells of graft.has direct cytotoxic effect on the cells of graft. A number of cytokines promote graft rejection by A number of cytokines promote graft rejection by

inducing expression of class – I or class – II MHC inducing expression of class – I or class – II MHC molecule on graft cell.molecule on graft cell.

The interferon (α, The interferon (α, and and ), TNF – α and TNF - ), TNF – α and TNF - all all increases class – I MHC expression, and IFN - increases class – I MHC expression, and IFN - increases increases class – II MHC expression as well.class – II MHC expression as well.

Effector Mechanisms of Effector Mechanisms of Allograft RejectionAllograft Rejection

Hyperacute RejectionHyperacute Rejection Acute RejectionAcute Rejection Chronic RejectionChronic Rejection

Hyperacute RejectionHyperacute Rejection Characterized by thrombotic Characterized by thrombotic

occlusion of the graftocclusion of the graft Begins within minutes or hours after Begins within minutes or hours after

anastamosisanastamosis Pre-existing antibodies in the host Pre-existing antibodies in the host

circulation bind to donor endothelial circulation bind to donor endothelial antigensantigens

Activates Complement CascadeActivates Complement Cascade Xenograft ResponseXenograft Response

Hyperacute RejectionHyperacute Rejection

1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation

Acute RejectionAcute Rejection

Vascular and parenchymal injury Vascular and parenchymal injury mediated by T cells and antibodies mediated by T cells and antibodies that usually begin after the first that usually begin after the first week of transplantation if there is no week of transplantation if there is no immunosuppressant therapyimmunosuppressant therapy

Incidence is high (30%) for the first Incidence is high (30%) for the first 90 days90 days

Acute RejectionAcute Rejection

1.1. T-cell, macrophage and Ab mediated,T-cell, macrophage and Ab mediated,

2.2. myocyte and endothelial damage, myocyte and endothelial damage,

3.3. InflammationInflammation

Chronic RejectionChronic Rejection

Occurs in most solid organ transplantsOccurs in most solid organ transplants HeartHeart KidneyKidney LungLung LiverLiver

Characterized by fibrosis and vascular Characterized by fibrosis and vascular abnormalities with loss of graft abnormalities with loss of graft function over a prolonged period.function over a prolonged period.

Chronic RejectionChronic Rejection

1.1. Macrophage – T cell mediatedMacrophage – T cell mediated

2.2. Concentric medial hyperplasiaConcentric medial hyperplasia

3.3. Chronic DTH reactionChronic DTH reaction

Tissue and Organ Tissue and Organ TransplantationTransplantation

Today it is possible to transplant many Today it is possible to transplant many different organs and tissues including.different organs and tissues including. Most common transplantation is blood Most common transplantation is blood

transfusion.transfusion. Bone Marrow transplantationBone Marrow transplantation Organs : Heart, kidneys, pancrease, Organs : Heart, kidneys, pancrease,

lungs, liver and intestines.lungs, liver and intestines. Tissues : include bones, corneas, skin, Tissues : include bones, corneas, skin,

heart values, veins, cartilage and other heart values, veins, cartilage and other connective tissues.connective tissues.

Most Common Most Common TransplantationTransplantation

-Blood Transfusion--Blood Transfusion-

Transfuse Not transfused

Bone Marrow Bone Marrow TransplantationTransplantation

Used for Leukemia, Anemia and Used for Leukemia, Anemia and immunodeficiency, especially severe combined immunodeficiency, especially severe combined immunodeficiency (SCID).immunodeficiency (SCID).

About 10About 1099 cells per kilogram of host body weight, cells per kilogram of host body weight, is injected intravenously into the recipients.is injected intravenously into the recipients.

Recipient of a bone marrow transplant is Recipient of a bone marrow transplant is immunologically suppressed before grafting.immunologically suppressed before grafting.

Eg. Leukemia patients are often treated with Eg. Leukemia patients are often treated with cyclo-phosphamide and total body irradiation to cyclo-phosphamide and total body irradiation to kill all cancerous cells.kill all cancerous cells.

Because the donor bone marrow contains Because the donor bone marrow contains immunocompetent cells, the graft may reject the immunocompetent cells, the graft may reject the host, causing graft versus host disease (GVHD).host, causing graft versus host disease (GVHD).

Graft vs. Host DiseaseGraft vs. Host Disease

Caused by the reaction of grafted Caused by the reaction of grafted mature T-cells in the marrow mature T-cells in the marrow inoculum with alloantigens of the hostinoculum with alloantigens of the host

Acute GVHDAcute GVHD Characterized by epithelial cell death in Characterized by epithelial cell death in

the skin, GI tract, and liverthe skin, GI tract, and liver Chronic GVHDChronic GVHD

Characterized by atrophy and fibrosis of Characterized by atrophy and fibrosis of one or more of these same target organs one or more of these same target organs as well as the lungsas well as the lungs

Heart Transplantation :Heart Transplantation : First heart transplant in South Africa by Dr. Christian First heart transplant in South Africa by Dr. Christian

Barnard in 1964.Barnard in 1964. One year survival rate is >80%.One year survival rate is >80%. HLA matching is desirable but not often possible, because HLA matching is desirable but not often possible, because

of the limited supply of heart and the urgency of the of the limited supply of heart and the urgency of the procedure.procedure.

Lung Transplantation :Lung Transplantation : First attempt in 1963 by Hardy and Co - workers.First attempt in 1963 by Hardy and Co - workers. First successful transplantation by Toronto group in 1983.First successful transplantation by Toronto group in 1983. In conjunction with heart transplantation, to treat diseases In conjunction with heart transplantation, to treat diseases

such as cystic fibrosis and emphysema or acute damage to such as cystic fibrosis and emphysema or acute damage to lungs.lungs.

First year survival rate is about 60%.First year survival rate is about 60%.

Kidney Transplantation :Kidney Transplantation : Diseases like diabetes and various type of nephritis Diseases like diabetes and various type of nephritis

can be elleviated by kidney transplantation.can be elleviated by kidney transplantation. Survival rate after one year transplantation is Survival rate after one year transplantation is

>90%.>90%. 25,000 candidates are waiting for kidney 25,000 candidates are waiting for kidney

transplantation.transplantation.

Liver transplantation :Liver transplantation : It treat congenital defects and damage from viral It treat congenital defects and damage from viral

(hepatitis) or chemical agents. (Chronic alcoholism).(hepatitis) or chemical agents. (Chronic alcoholism). Liver one year survival exceeds 75% and five year is Liver one year survival exceeds 75% and five year is

70%.70%.

Pancrease Transplantation :Pancrease Transplantation : Offers a cure for diabetes mellitus.Offers a cure for diabetes mellitus. Graft survival is 72% at one year.Graft survival is 72% at one year. Further improved if a kidney is transplanted Further improved if a kidney is transplanted

simultaneously.simultaneously. Overall goal - to prevent the typical diabetic Overall goal - to prevent the typical diabetic

secondary complications.secondary complications.

Skin grafting :Skin grafting : It is used to treat burn victims.It is used to treat burn victims. In severe burn, grafts of foreign skin may be In severe burn, grafts of foreign skin may be

used and rejection must be prevented by the use used and rejection must be prevented by the use

of immunosuppressive therapy. of immunosuppressive therapy.

Xenogeneic Xenogeneic TransplantationTransplantation

A major barrier to xenogeneic A major barrier to xenogeneic transplantation is the presence of transplantation is the presence of natural antibodies that cause natural antibodies that cause hyperacute rejection. hyperacute rejection.

Immunosuppressive Immunosuppressive AgentsAgents

Immunosuppression can be brought Immunosuppression can be brought about by 3 different ways :-about by 3 different ways :-

Surgical ablationSurgical ablation Total Lymphoid IrradiationTotal Lymphoid Irradiation Immunosuppressive drugsImmunosuppressive drugs

Immunosuppressive Immunosuppressive DrugsDrugs

Three main immunosuppressant drugs Three main immunosuppressant drugs CyclosporinsCyclosporins act by inhibiting T-cell act by inhibiting T-cell

activation, thus preventing T-cells from activation, thus preventing T-cells from attacking the transplanted organ. attacking the transplanted organ.

AzathioprinesAzathioprines disrupt the synthesis of DNA disrupt the synthesis of DNA and RNA and cell division. and RNA and cell division.

CorticosteroidsCorticosteroids such as prednisolone such as prednisolone suppress the inflammation associated with suppress the inflammation associated with transplant rejection.transplant rejection.

Immunosuppressants can also be classified Immunosuppressants can also be classified depending on the specific transplant:depending on the specific transplant:

BasiliximabBasiliximab in combination with cyclosporin in combination with cyclosporin and corticosteroids, in kidney transplants. and corticosteroids, in kidney transplants.

DaclizumabDaclizumab in combination with cyclosporin in combination with cyclosporin and corticosteroids, in kidney transplants.and corticosteroids, in kidney transplants.

muromonabmuromonab CD3 (Orthoclone OKT3) along CD3 (Orthoclone OKT3) along with cyclosporin, in kidney, liver and heart with cyclosporin, in kidney, liver and heart transplants.transplants.

TacrolimusTacrolimus is used in liver transplants and is is used in liver transplants and is under study for kidney, bone marrow, heart, under study for kidney, bone marrow, heart, pancreas, pancreatic island cell, and small pancreas, pancreatic island cell, and small bowel transplantation.bowel transplantation.

Some immunosuppressants are also used to Some immunosuppressants are also used to treat a variety of autoimmune diseases:treat a variety of autoimmune diseases: AzathioprineAzathioprine in treatment of rheumatoid arthritis , in treatment of rheumatoid arthritis ,

chronic ulcerative colitis but limited value.chronic ulcerative colitis but limited value. CyclosporinCyclosporin is used in heart, liver, kidney, pancreas, is used in heart, liver, kidney, pancreas,

bone marrow and heart/lung transplantation. Also used bone marrow and heart/lung transplantation. Also used to treat psoriasis and rheumatoid arthritis, multiple to treat psoriasis and rheumatoid arthritis, multiple sclerosis, diabetes and myesthenia gravis. sclerosis, diabetes and myesthenia gravis.

Glatiramer acetateGlatiramer acetate is used in treatment of relapsing- is used in treatment of relapsing-remitting multiple sclerosis. remitting multiple sclerosis.

MycophenolateMycophenolate is used along with cyclosporin in is used along with cyclosporin in kidney, liver and heart transplants. Also used to kidney, liver and heart transplants. Also used to prevent the kidney problems associated with lupus prevent the kidney problems associated with lupus erythematosus. erythematosus.

SirolimusSirolimus in combination with cyclosporin and in combination with cyclosporin and corticosteroids, in kidney transplants. The drug is also corticosteroids, in kidney transplants. The drug is also used for the treatment of psoriasis.used for the treatment of psoriasis.

Immunosuppressive Immunosuppressive TherapyTherapy

Monoclonal antibodies Monoclonal antibodies To suppress the activity of subpopulation of T-cells.To suppress the activity of subpopulation of T-cells. To block co-stimulatory signals.To block co-stimulatory signals. Ab to the CD3 molecule of TCR (T cell receptor) complex Ab to the CD3 molecule of TCR (T cell receptor) complex

results in a rapid depletion of mature T-cells from the results in a rapid depletion of mature T-cells from the circulation. circulation.

Ab specific for the high-affinity IL-2 receptor is expressed Ab specific for the high-affinity IL-2 receptor is expressed only on activated T-cell, blocks proliferation of T-cells only on activated T-cell, blocks proliferation of T-cells activated in response to the alloantigens of the graft.activated in response to the alloantigens of the graft.

To treat donor’s bone marrow before it is transplanted. To treat donor’s bone marrow before it is transplanted. Molecules present on particular T-cells subpopulation may Molecules present on particular T-cells subpopulation may

also be targeted for immunosuppressive therapy.also be targeted for immunosuppressive therapy. Antibody to CD4 shown to prolong graft survival. Antibody to CD4 shown to prolong graft survival. Ab specific for implicated cytokine can prolong the survival Ab specific for implicated cytokine can prolong the survival

of graft.of graft.

ConclusionConclusion More than 50,000 people, waiting for compatible More than 50,000 people, waiting for compatible

donor. For ethical an practical reasons, species donor. For ethical an practical reasons, species closely related to human such as Chimpanzee closely related to human such as Chimpanzee have not been widely used.have not been widely used.

Xenogeneic transplantation may be major issue of Xenogeneic transplantation may be major issue of research xenograft technology including research xenograft technology including genetically modified animal may become a new genetically modified animal may become a new source of organ supply.source of organ supply.

Side effects of immunosuppressive agent use for Side effects of immunosuppressive agent use for graft need a change of specificity in action and graft need a change of specificity in action and avoiding general immune suppression.avoiding general immune suppression.

Techniques such as transgenic animal production Techniques such as transgenic animal production and wide range of research in this field hope to and wide range of research in this field hope to result in opening a new window for the process of result in opening a new window for the process of transplantation immunology.transplantation immunology.

References

•Immunology by – Janis Kuby•Immunology by – Abdul Abbas•Immunology by – Roitt•Fundamental Immunology by – William E. Paul

Information from –•www.organtransplants.org•www.transweb.org•www.organdonor.web

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