Question

 

1)     Discuss the different types of grafts from immunological perspective and how immune system responds to them.

2)     Describe the principles, not therapy details, of reducing graft rejection.

Answer 1

question 1:

ans:Transplantation is the act of transferring cells, tissues, or organs from one site to another. The malfunction of an organ system can be corrected with transplantation of an organ (eg, kidney, liver, heart, lung, or pancreas) from a donor. However, the immune system remains the most formidable barrier to transplantation as a routine medical treatment. The immune system has developed elaborate and effective mechanisms to combat foreign agents. These mechanisms are also involved in the rejection of transplanted organs, which are recognized as foreign by the recipient's immune system.

The degree of immune response to a graft depends partly on the degree of genetic disparity between the grafted organ and the host. Xenografts, which are grafts between members ofdifferent species, have the most disparity and elicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the body to another (eg, skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are grafts between genetically identical individuals (eg, monozygotic twins), also undergo no rejection. Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation. The degree to which allografts undergo rejection depends partly on the degree of similarity or histocompatibility between the donor and the recipient. [3, 4, 5] The degree and type of response also vary with the type of the transplant. Some sites, such as the eye and the brain, are immunologically privileged (ie, they have minimal or no immune system cells and can tolerate even mismatched grafts). Skin grafts are not initially vascularized and so do not manifest rejection until the blood supply develops. The heart, kidneys, and liver are highly vascular organs and lead to a vigorous cell mediated response in the host.

question 2:

ans:Mechanisms of rejection =The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts. The rejection reaction consists of the sensitization stage and the effector stage.

Sensitization stage In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the alloantigens expressed on the cells of the foreign graft. Two signals are needed for recognition of an antigen; the first is provided by the interaction of the T cell receptor with the antigen presented by MHC molecules, the second by a costimulatory receptor/ligand interaction on the T cell/APC surface. Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively), has been studied the most. [6] In addition, cytotoxic T lymphocyte– associated antigen-4 (CTLA4) also binds to these ligands and provides an inhibitory signal. Other costimulatory molecules include the CD40 and its ligand CD40L (CD154). Typically, helices of the MHC molecules form the peptide-binding groove and are occupied by peptides derived from normal cellular proteins. Thymic or central tolerance mechanisms (clonal deletion) and peripheral tolerance mechanisms (eg, anergy) ensure that these selfpeptide MHC complexes are not recognized by the T cells, thereby preventing autoimmune responses. At least 2 distinct, but not necessarily mutually exclusive, pathways of allorecognition exist, the direct and indirect pathways. Each leads to the generation of different sets of allospecific T cell clones.

Clinical Stages of Rejection

• Hyperacute rejection
• Acute rejection
• Chronic rejection

The following factors increase the risk of chronic rejection:

• Previous episode of acute rejection
• Inadequate immunosuppression
• Initial delayed graft function
• Donor-related factors (eg, old age, hypertension)
• Reperfusion injury to organ
• Long cold ischemia time
• Recipient-related factors (eg, diabetes, hypertension, hyperlipidemia)
• Posttransplant infection (eg, cytomegalovirus [CMV])