Immunology. Anas Abu-Humaidan M.D. Ph.D. Transplant immunology+ Secondary immune deficiency

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1 Immunology Anas Abu-Humaidan M.D. Ph.D. Transplant immunology+ Secondary immune deficiency

2 Transplant Immunology Transplantation is the process of moving cells, tissues or organs from one site to another for the purpose of replacing or repairing damaged or diseased organs and tissues. The immune system poses a significant barrier to successful organ transplantation when tissues/organs are transferred from one individual to another. Rejection is caused by the immune system identifying the transplant as foreign, triggering a response that will ultimately destroy the transplanted organ or tissue. Donor and recipient are carefully matched prior to transplantation to minimise the risk of rejection. Immunosuppressive drugs are used to prevent and to treat transplant rejection by dampening the overall immune response. Research on the immunological mechanisms of rejection will help improve cross matching, diagnosis and treatment, as well as facilitating the discovery of novel strategies for preventing rejection.

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4 Types of transplantation Autograft Transplantation of cells, tissues or organs between sites within the same individual e.g. skin grafts in burn patients. Allograft Transplantation of organs or tissues from a donor to a non-genetically identical individual of the same species. Allografts are the most common type of transplant. Isograft - Transplantation of organs or tissues from a donor to a genetically identical individual (i.e. identical twin). Xenograft Transplantation of an organ or tissue between two different species. Pig valves, for example, are commonly used to repair or replace a defective heart valve in humans.

5 Remember: Each MHC molecule on the cell surface displays a molecular fraction of a protein, called an epitope. The presented antigen can be either self or non-self, thus preventing an organism's immune system targeting its own cells Transplant Immunology The complex mechanisms of immunity, which under normal circumstances work to identify foreign microbes and direct the immune system to destroy them, pose a significant barrier to successful transplantation. Rejection of a transplant occurs in instances where the immune system identifies the transplant as foreign, triggering a response that will ultimately destroy the transplanted organ or tissue. The Human Leukocyte Antigen (HLA) complex is a group of genes that encode the proteins responsible for identifying foreign agents to the immune system. Also referred to as MHC. Any cell not displaying self specific HLA proteins will be identified as non-self by the immune system and will be treated as a foreign invader. Identification of these non-self antigens will trigger an immune response and will stimulate the production of antigen specific antibodies that mark cells for destruction by the immune system and help amplify the immune response.

6 Rejection of graft (types/stages) Hyperacute rejection occurs within minutes or hours after a transplantation and is caused by the presence of preexisting antibodies of the recipient, that match the foreign antigens of the donor, triggering an immune response against the transplant. The antibodies react with cells in the blood vessels of the graft, causing blood clots to form, which will prevent blood supply from reaching the graft resulting in immediate rejection of the transplant

7 Rejection of graft (types/stages) Acute rejection occurs within the first 6 months after transplantation. Some degree of acute rejection will occur in all transplantations, except between identical twins.

8 Dendritic cells in brown within lymphocyte aggregates Dendritic cells in brown within airway epithelium

9 Rejection of graft (types/stages) Chronic rejection. Repeated episodes of acute rejection can ultimately lead to chronic rejection of the graft and failure of the transplant. Chronic rejection commonly manifests as scarring of the tissue or organ which can occur months to years after acute rejection has subsided.

10 Compatibility testing (matching) Rejection can be minimised by carefully matching the donor and recipient for compatibility prior to transplantation. The better matched the donor and recipient are the more successful the transplantation is likely to be. Several tests are commonly done including: ABO blood group compatibility The donor and recipient are tested for compatible blood groups. Tissue typing A blood sample is taken from the recipient to identify the HLA antigens present on the surface of the their cells to help find a compatible donor. Siblings offer the best donors usually. Cross matching Blood samples are taken from both the recipient and donor, and the cells of the donor are mixed with the blood serum of the recipient. If the recipient s antibodies attack the donor cells, they are considered a positive match and transplantation will not be suitable due to increased risk of hyperacute rejection. Panel reactive antibody test The blood serum of patients awaiting transplantation are tested for reactive antibodies against a random panel of cells. The more HLA antibodies present, the higher he panel reactive antibody (PRA) level denoted to the patient, and the greater the chance of graft rejection.

11 Immunosuppressive drugs To reduce the risk of transplant rejection, patients are treated with immunosuppressive drugs that will dampen their immune response. Immunosuppressive drugs are given in two phases; an initial induction phase involving a high dose, and a later maintenance phase which involves using the drug in the long term at a lower dose. The combination of drugs, and dosage given, will vary depending on the type of transplant and the chosen treatment regime. Examples include: The calcineurin inhibitors cyclosporine and tacrolimus, steroids, Target of Rapamycin Inhibitors, Azathioprine.

12 Graft vs host disease (GVHD) Allogeneic hematopoietic stem cell transplantation (HSCT) is used for treatment of several hematological malignancies as well as immune disorders. GVHD is initiated by mature CD4 + and/or CD8 + T cells that accompany allogeneic HSCT. GVHD can occur in HLA identical individuals, due to differences in minor histocompatibility antigens (miha). Many miha are encoded on the Y chromosome. Diagnosis of GVHD is based on signs and symptoms the affected tissue, and will involve tests that affect

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16 Immunodeficiency (ID)

17 Immunodeficiency (ID) ID can be defined as failure of the immune system to protect the body from infections or tumors as a result of defect or failure of one or more of the immune system components. ID can be classified into primary disorders (genetic defects, rare) and secondary disorders (acquired, might be treated by the management of the underlying cause). Healthy individuals are prone to common infections as well particularly during early life when the immune system has not developed fully. The repeated or unusual infections is an important sign of ID. The type of infection can give clues to the cause and degree of ID.

18 Overview of the primary ID 1 2 % of the population may be affected with a PI when all types and varieties are considered

19 Immunodeficiency (ID) The type of infection can give clues to the cause and degree of ID. For example: Defective antibody production causes increased susceptibility, mostly to bacterial infections (that typically involve the upper and lower respiratory tract (otitis, sinusitis, and pneumonia), whereas Defects of late complement components (C5-C9) are associated with recurrent and invasive neisserial infections.

20 Overview of the Secondary ID Secondary immunodeficiencies are far more common than primary immunodeficiencies Secondary immunodeficiencies result from a variety of factors that can affect a host with an intrinsically normal immune system, including infectious agents, drugs, metabolic diseases, and environmental conditions.

21 Secondary ID - Malnutrition Worldwide, protein-calorie malnutrition is the most common cause of immunodeficiency Malnutrition can result from limited access to food sources and chronic diseases that induce cachexia, such as neoplastic diseases. T-cell production and function decrease in proportion to the severity of hypoproteinemia.

22 Secondary ID - Malnutrition The deficiency of micronutrients like zinc and ascorbic acid (vitamin C) contributes to increased susceptibility to infections through the weakening of barrier mucosa, therefore facilitating a pathogen's invasiveness. Vitamin D appears to be necessary in the macrophage activity against intracellular pathogens, remarkably Mycobacterium tuberculosis

23 Secondary ID Extremes of Age Neonates have an increased susceptibility to common and opportunistic infections and sepsis compared with older children. In early life there are fewer marginal-zone B cells in lymphoid tissue and a decreased expression of CD21 on B cells, thus limiting the ability of B cells to develop specific responses Although they can develop humoral responses to some antigens after exposure in utero, impaired immunity in newborns can be attributed to the relative lack of maturity of secondary lymphoid organs, including the lymphoid tissue associated to mucosa in the gastrointestinal and respiratory tracts. This immaturity is related to the absence of memory cell development because of the relative isolation provided by the maternal environment.

24 Secondary ID Extremes of Age Among the elderly, some subjects experience malignancies and an excessive number of infections caused by viruses and bacteria, reflecting a decrease in the immune defenses, particularly in the cellular compartment. Decreased delayed-type hypersensitivity skin reactions and decreased lymphocyte proliferative responses to mitogens can be demonstrated in this patient population. The innate immunity might be compromised in the elderly, with increased breakdown of skin and mucosal barriers and slow healing processes caused by metabolic and endocrinologic changes associated with aging. A diminished production of hematopoietic growth factors has been postulated to occur in the elderly, resulting in decreased ability to upregulate the production and function of macrophages and neutrophils

25 Secondary ID Metabolic Disorders Diabetes mellitus and uremia resulting from kidney or liver disease are 2 common metabolic disorders with known deleterious effects on immunity. Optimal control of the metabolic abnormality usually leads to improved immune function. The defective immune functions reported in patients with diabetes mellitus include defective phagocytosis and macrophage chemotaxis in vitro, T-cell anergy demonstrated by delayed hypersensitivity skin tests, and poor lymphoproliferative response to mitogens caused by chronic exposure to hyperglycemia

26 Secondary ID Metabolic Disorders The diminished capacity to generate memory antibody responses, regardless of repeated vaccination, and defective phagocyte chemotaxis and microbicidal activity in vitro are examples of the immune defects present in uremic patients

27 Secondary ID Drugs The use of drugs to ameliorate undesirable immune responses is common in clinical practice as a consequence of the increasing prevalence of inflammatory conditions. These diseases include the categories of autoimmune disorders, allergic disorders, transplant rejection, and graft-versus-host disease (GvHD). The overall results are decreased cytokine production (IL-1, IL- 6, and TNF-α) and impaired leukocyte chemotaxis, cell adhesion, phagocytosis, and lymphocyte anergy. Examples of infections following immunosuppressive drugs are oral candidiasis, a frequent complication of the use of inhaled steroids, and herpes zoster disease, which often presents with chronic use of systemic corticosteroids.

28 Secondary ID Infectious diseases Transient periods of immunosuppression have been associated with viral infections. infections with measles virus, CMV, and influenza virus can induce lymphopenia and also T-cell anergy; however, these are transient and usually less severe than the immunodeficiency seen in AIDS.

29 Secondary ID HIV Infection HIV infection begins with the binding of the HIV gp120 protein to the CD4 molecule and the chemokine receptor CCR5 on target cells. Infected cells migrate to the lymph nodes, where initial replication and infection of nearby CD4 + T cells occur During acute HIV infection, the gut-associated lymphoid tissue is severely depleted, with predominant loss of memory CD4 + T cells and with high viremia and immune activation HIV induces T-cell lymphopenia through several mechanisms: HIV-induced apoptosis, viral cytopathic effect, apoptosis caused by nonspecific immune activation, and cytotoxicity to HIV-infected cells.

30 When the peripheral CD4+ T-cell count is less than 200 cells/ml, the patient can present with any of a number of infections that define AIDS, such as Pseudomonas jiroveci induced pneumonia, histoplasmosis, toxoplasmosis, and coccidioidomycosis A small proportion of HIV-infected patients remain asymptomatic and do not have AIDS. These patients are called long-term nonprogressors and have been the focus of multiple studies to understand the basis of their protection. Those who maintain low levels of HIV (ie, <50 RNA copies/ml) without treatment are called elite controllers

31 Secondary ID A detailed clinical history might uncover the condition affecting the immune system, such as infection, malnutrition, age extremes, concomitant metabolic or neoplastic diseases, use of immunosuppressive drugs, and exposure to harsh environmental conditions. Because of its prevalence and clinical progression, HIV infection should be considered and ruled out.