Transplantation and tumor immunology

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Transplantation Immunology

The immune response has evolved as a way of discriminating between self and nonself

Once foreignness has been established, immune response proceeds toward its ultimate goal of destroying the foreign material

Be it a microorganism or its product, a substance present in the environment, or a tumor cell

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Transplantation Immunology, cont.Transplantation

Transfer of tissue or organ from one individual to another whereas transfusion refers to transfer of blood from one individual to another

Antibodies are responsible for transfusion reactions;

Rejection of transplanted tissue is mediated predominantly by T cells

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Transplantation Immunology, cont.

Gradations in relationships of transplantation from donor to recipient are:

Autograft

A graft or transplant from one area to another on the same individual

Transplantation of normal skin from one area of an individual to a burned area of the same individual

Graft is recognized as autologous (self)

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Transplantation Immunology, cont.No immune response is induced against itBarring technical difficulties in the transplantation, the graft will survive or take in its new location

Isograft or SyngraftGraft or transplantation of cells, tissue or organ from one individual to another individual who is syngeneic (genetically identical) to the donor

Transplantation of a kidney from one identical (homozygotic) twin to the other

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Transplantation Immunology, cont.The recipient who is genetically identical to the donor recognizes the donor’s tissue as self

And does not mount an immune response against it

The 2 individuals i.e. donor and recipient are histocompatible

Allograft

Graft or transplant from one individual to a genetically dissimilar individual of the same species

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Since all individuals of a given outbreed species, except monozygotic twins, are allogeneic (genetically dissimilar), regardless of how closely they may be related

Graft is recognized by recipient as foreign and is immunologically rejected

The donor and recipient, in this case, are nonhistocompatible or histoincompatible

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Xenograft

Graft between a donor and a recipient from different species

Transplant is recognized as foreign and immune response mounted against it will destroy or reject graft

Donor and recipient are again described as histoincompatible

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Role of Immune Response in Allograft RejectionMouse skin with black hair transplanted onto the back of a white-haired mouse (between allogeneic donor and recipient) appears normal for 1 or 2 wksAfter approx. 2 wks, transplant begins to be rejected Is completely sloughed off within a few days, process is called first-set rejection

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If after this rejection, recipient is transplanted with another piece of skin from same initial donor, process of rejection is accelerated second-set rejection

The graft is sloughed quicker, within about a week of second transplant

In contrast, a piece of skin from a genetically different strain grafted onto this same mouse is rejected with first-set kinetics

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Thus, second-set rejection is an expression of specific immunologic memory for antigens expressed by the graft

Participation of T cells in the rejection response can be shown by transferring T cells from an individual sensitized to an allograft into a normal syngeneic recipient

If the second recipient is transplanted with same allograft that was used on the original T-cell donor, a second-set rejection ensues

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Many other lines of evidence establish immunologic nature of graft rejection

Histologic examination of the site of rejection reveals lymphocytic and monocytic cellular infiltration reminiscent of delayed-type hypersensitivity reaction

Both CD4+ and CD8+ cells are present at the site

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Individuals that lack T lymphocytes such as athymic or nude, mice or humans with DiGeorge syndrome) do not reject allografts or xenografts

Process of rejection slows down considerably or does not occur at all in immunosupressed individuals

Has been conclusively demonstrated that specific T cells and circulating antibodies are induced to an allograft or a xenograft

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However, T cells constitute major immunologic component responsible for rejection of allograft tissues

Certain antibodies that are not effective in the process of graft rejection compete with T cells for transplantation antigens, thereby blocking the process of rejection mediated by T cells and enhancing the survival of graft enhancing antibodies

Relevance of this phenomenon still unclear

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Clinical Characteristics of Allograft Rejection

Fall into 3 major categories:

Hyperacute rejection

Acute rejection

Chronic rejection

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Hyperacute rejectionOccurs within a few minutes to a few hours of transplantationResult of destruction of transplant by preformed antibodies such as in ABO blood group incompatibilityNo transplantation will be performed, or preformed antibodies to the graft, synthesized as a result of previous transplantations, blood transfusions, or pregnancies

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Transplantation Immunology, cont.These antibodies activate complement system followed by platelet activation and deposition causing swelling and interstitial hemorrhage in the transplanted tissue, which decrease the flow of blood thro tissue

Thrombosis with endothelial injury fibrinoid necrosis are often seen

Recipient may have fever, leukocytosis and produce little or no urine

Urine may contain various cellular elements such as erythrocytes

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Transplantation Immunology, cont.Cell mediated immunity is not involved at all

At present there is no therapy for successful prevention or termination of hyperacute rejection

Acute Rejection

Seen in a recipient who has not previously been sensitized to transplant

Cell mediated immunity mediated by T cells is the primary cause of acute rejection

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Common type of rejection experienced by individuals for whom transplanted tissue is a mismatch

Or who receive an allograft and insufficient immunosuppressive treatment to prevent rejection

Reaction may begin a few days after transplantation of a kidney, with a complete loss of kidney function within 10-14 days

Accompanied by a rapid decrease in renal function

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Enlargement and tenderness of grafted kidney, a rise in serum creatinine levels, a fall in urine output, decreased renal blood flow are characteristic

Histologically, CMI manifested by intense filtration of lymphocytes and macrophages, is taking place at rejection site

May be reduced by immunosuppressive therapy such as antilymphocytic serum, corticosteroids, or other drugs

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Transplantation Immunology, cont.Chronic rejection

Caused by both antibody and cell-mediated immunity occurs in allograft transplantation months after transplanted tissue has assumed its normal function

In kidney transplantation, is characterized by slow, progressive renal failure

Histologically, is accompanied by proliferative inflammatory lesions of small arteries, thickening of glomerular basement membrane and interstitial fibrosis

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Because damage caused by immune injury has already taken place, immunosuppressive therapy at this point is useless

Little can be done to save the graft

Rate, extent and underlying mechanisms of rejection may vary depending on the transplanted tissue and site of transplanted graft

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Recipient circulation, lymphatic drainage, expression of strong antigens on the graft and several other factors determine rejection rate

Bone marrow and skin grafts are very sensitive to rejection compared to heart, kidney and liver

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Prolongation of Allografts

Several measures are taken during transplantation that are aimed at prolonging graft survival; mostly suppress entire immune response in a non-antigen-specific way

Anti-inflammatory agents – corticosteroids such as prednisolone

Antimetabolites – azathioprine, mercaptopurine, chlorambucil and cyclophosphamide

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Cytotoxic and blocking agents – antilymphocytic serum (ALS), antilymphocytic globulins (ALGs), steroids, alkylating agents, X-rays and antibiotics such as actinomycin D

Cyclosporine and FK 506

Total lymphoid irradiation

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Transplantation Immunology, cont.Graft-versus-host (GVH) reactions

Transplantation of immunocompetent lymphocytes from a donor to a genetically different recipient can result in a reaction mounted by the grafted lymphocytes against recipient’s tissueIs particularly important in cases where immunocompetent lymphoid cells are transplanted into individuals who are immunologically incompetent, therefore can not reject transplanted cells

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GVH disease may occur in bone marrow transplant recipients even if the donor and recipient are perfectly HLA-matchedThis is probably due to minor, non-HLA-coded, transplantation antigens recognized by donor T cellsIn humans, may produce splenomegally, enlarged liver and lymph nodes, diarrhoea, anemia, weight loss and other disorders in which underlying causes are inflammation and destruction of tissue

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Transplantation Immunology, cont.Initiated by the transferred T lymphocytes from donor, which recognize recipient’s transplantation antigens as foreign

Donor T cells thus become activated as in an allograft response

In GVH disease, however, most of inflammatory cells that participate in the reaction and that are mainly responsible for destruction of tissue, are host cells recruited to site of reaction by lymphokines released by donor’s lymphocytes

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Tumor ImmunologyExistence of an immune response against a tumor is based on changes in the surface components of malignant cell that do not occur in its normal counterpart

And that give rise to structures that are antigenic

Goals

To elucidate the immunologic relationship between the host and the tumor and

To utilize immune response to tumors for purpose of diagnosis, prophylaxis and therapy

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Tumor Immunology, cont.

Tumor Antigens

Some antigens on the surface of malignant cells may consist of structures that are unique to cancerous cells and are not present on their normal counterparts tumor-specific transplantation antigens (TSTAs) or simply tumor-specific antigens (TSAs)

Other tumor antigens may represent structures that are common to both malignant and normal cells but are masked on the normal cells and become unmasked on malignant cells

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Tumor Immunology, cont.Still other antigens on tumor cells represent structures that are qualitatively not different from those found on normal cells but that are over expressed – present at significantly increased numbers on the cancer cell as products of cellular oncogenes tumor-associated antigens (TAAs)

High levels of a growth factor receptor due to increased expression of the neu oncogene products found in a number of human breast cells, and elevated ras oncogene products present on some human prostate cancer cells

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Still other antigens on malignant cells represent structures that are present on fetal or embryonic cells but disappear from normal adult cells oncofetal or oncodevelopmental antigens

Classification of tumor antigensMay be classified into 4 major categories

Differ in both factors that induce malignancy and immunochemical properties of tumor antigens

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Antigens of tumors induced by chemical or physical Carcinogens

Exhibits a unique antigen specificity

Cells of a given tumor, arising from a single transformed cell, all share common antigens, but different tumors, even if induced by the same carcinogen, are antigenically distinct from one another

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Tumor Immunology, cont.If the chemical carcinogen methylcholanthrene is applied in identical manner to skin of two genetically identical animals, or on two similar sites on the same individual, cells of developing tumors (sarcomas) will exhibit antigens unique to each tumor, with no immunologic cross-reactivity between tumors

There is little or no cross-reactivity between physically induced tumors, such as those induced by UV light or by X irradiation

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Tumor Immunology, cont.Absence of cross-reactivity is probably due to random mutations induced by chemical or physical carcinogens leading to a large array of different antigensSince most human and animal tumors are attributed to chemical and physical environmental factors such as radiation, smoke, and tar, these tumors, which lack immunologic cross-reactivity, are unfortunately not expected to be amenable to diagnosis, prophylaxis or therapy by immunologic means

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Antigens of virally induced tumors

Animal studies have shown that tumors induced by DNA or RNA oncogenic virus exhibit extensive immunologic cross-reactivity

Because any particular oncogenic virus induces expression of same antigens in a tumor, regardless of tissue origin or animal species

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DNA viruses such as polyoma, SV40 and Shope papilloma virus induce tumors that exhibit extensive cross-reactivity within each virus group

Many leukemogenic viruses such as Raucher leukemia virus, induce formation of tumors that exhibit cross-reactivity not only within each virus group but also between some groups

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Tumor Immunology, cont.There is considerable circumstantial evidence to suggest that several human cancers such as Burkitt’s lymphoma, nasopharyngeal carcinoma, T-cell leukemia, and hepatocellular carcinoma are caused by viruses

Cross-reactivity is well established for cell surface antigens of Burkitt’s lymphomas or of neuroblastomas from different patients

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Colon carcinoma cells obtained from different patients also exhibit immunologic cross-reactivity, as do melanoma cells from different patientsSome antigens of virally induced tumors are encoded by the virus, but they are distinct from virion antigens tumor-associated antigens (TAA)Occasionally, virally induced tumors may express oncofetal antigens, encoded by the host genome

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Tumor Immunology, cont.Oncodevelopmental tumor antigens

Many tumors express on their surface, or secrete into blood, products that are normally present during embryonic and fetal development, but that are either absent or present at very low levels in normal adult tissueThese structures are not immunogenic in the autochthonous (native or original) hostTheir presence can be detected by antisera prepared against them in allogeneic or xenogeneic animals

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Tumor Immunology, cont.E.g. Carcinoembryonic antigen (CEA) found primarily in serum of patients with cancers of gastrointestinal tract esp. cancer of colon

Elevated levels have also been detected in the circulation of patients with some types of lung cancer, pancreatic cancer and some types of breast and stomach cancer

However, elevated levels of CEA also detected in patients with emphysema, ulcerative colitis, and pancreatitis as well as in the sera of alcoholics and heavy smokers

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Tumor Immunology, cont.-fetoprotein (AFP), which is normally present at high concentrations in fetal and maternal serum but absent from serum of normal individuals

Rapidly secreted by cells of a variety of cancers and is found particularly in patients with hepatomas and testicular teratocarcinomas

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Association of oncodevelopmental antigens with a wide variety of tumor types strongly suggests that derepression of normal genes that are usually repressed in the normal adult individual is a concomitant malignancy

Antigens of spontaneous tumors

Spontaneous tumors are induced by unknown causes

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Tumor Immunology, cont.With recent advent of sensitive detection techniques, antibodies to autochthonous tumors have been found in patients with some tumors, most notably malignant melanoma

In some cases, antigens exhibit immunologic cross-reactivity, in other cases they do not

Thus, antigens of spontaneous tumors seem to resemble those of chemically or virally induced tumors with respect to immunologic specificity

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Immune response to tumors: humoral and cellular effector immune mechanisms in tumor cell destruction

Humoral mechanisms

Lysis by antibody and complement

Antibody-mediated and complement mediated opsonization

Antibody-mediated loss of tumor cell adhesion

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Cellular mechanisms

Destruction by cytotoxic cells

Antibody-dependent, cell-mediated cytotoxicity (ADCC)

Destruction by activated macrophages

Destruction by natural killer (NK) cells

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Role of immune response in the relationship between host and tumor

Tumors in immunosuppressed individuals

Tumors occur more frequently in immunosuppressed individuals than in their normal counterparts

Such tumors are predominantly but not exclusively lymphoproliferative malignancies

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Tumor Immunology, cont.Tumors in the immunocompetent host

Involvement of immune response in the host-tumor relationship is suggested by correlation between appearance of various immunologic effector mechanisms and state of resistance to transplanted tumors in experimental animals

There is a correlation between appearance of immune components at the site of tumor and regression of tumors in animals and humans

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Concomitant immunity is expressed by host’s ability to reject newly arising or transplanted tumors of same type, despite progression of primary tumor

Immune surveillance

Propounded by Thomas in 1950 and expanded by Burnet later

Theory remains controversial and unproven

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Limitations of effectiveness of immune response against tumors

Tumor resides in immunologically privileged site

Antigenic modulation of tumor antigens

Presence of enhancing or blocking factors

Suppressor T lymphocytes

Immune suppression by tumor cell products

Excessive tumor mass

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Immunodiagnosis

May be performed to achieve two separate goals

Immunological detection of antigens specific to tumor cells and

Assessment of host’s immune response to tumor

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Detection of tumor cells and their products by immunological meansMyeloma and Bence-Jones proteins e.g. plasma cell tumorAFP e.g. liver cancerCEA e.g. gastrointestinal cancersProstate-specific antigen (PSA)Immunological detection of other tumor cell markers e.g. enzymes and hormones

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Tumor Immunology, cont.Detection of tumor-specific antigens in the circulation or by immunoimaging

Detection of anti-tumor immune responseAnti-tumor antibodiesAnti-tumor cell-mediated immunity

Tumor immunoprophylaxisImmunization against tumor itself requires that tumor possesses specific antigens and that these antigens cross-react immunologically with any prepared vaccine

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Efficacy of immunoprophylaxis for protection of humans and animals against spontaneous tumors has not been sufficiently evaluated

Immunotherapy of tumors

Vaccination and adjuvant therapy

Cytokine therapy e.g. interferon , , , IL-2, IL-4, IL-5, IL-12, TNF, lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs)

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Tumor Immunology, cont.Anti-idiotype antibody therapy

Dramatic regression have recently been reported in several lymphoma patients

Immunotoxin therapyToxins such as ricin, or radioactive isotopes attached to tumor-specific antibodies are delivered specifically to tumor cells for direct killingExtent to which these immunotoxins will prove effective in the treatment of cancer remains to be established

Technology

Transplantation and tumor immunology