Graft rejection is the consequence of an immune response mounted by the recipient against the graft as a consequence of the incompatibility between tissue antigens of the donor and recipient. Cells that express class II MHC antigens (such as passenger leukocytes in the case of solid organ transplants) play a major role in sensitizing the immune system of the recipient. The sensitization of alloreactive helper T lymphocytes from the recipient is fol-lowed by their clonal expansion, which in turn is the cause of multiple immunological and inflammatory phenomena, some mediated by activated T lymphocytes and others mediated by antibodies, which eventually result in graft rejection.
Rejection episodes are traditionally classified as hyperacute, acute, and chronic, based primarily on the time elapsed between transplantation and the rejection episode.
This occurs usually within the first few hours posttransplantation and is mediated by pre-formed antibodies against ABO or MHC antigens of the graft. It is also possible that anti-bodies directed against other alloantigens such as vascular endothelial antigens may also play a role in this type of rejection. Once the antibodies bind to the transplanted tissues, re-jection can be caused either by activation of the complement system, which results in the chemotactic attraction of granulocytes and the triggering of inflammatory circuits, and/or by antibody-dependent cellular cytotoxicity (ADCC).
A major pathological feature of hyperacute rejection is the formation of massive in-travascular platelet aggregates leading to thrombosis, ischemia, and necrosis. The forma-tion of platelet thrombi probably results from several factors, including release of platelet-activating factor (PAF) from immunologically damaged endothelial cells and/or from activated neutrophils.
Hyperacute rejection episodes are untreatable and result in graft loss. With proper cross-matching techniques, this type of rejection should be almost 100% avoidable. How-ever, it must be noted here that the major limitation to xenogeneic transplantation (e.g., pig to human) is hyperacute rejection by antibodies to cellular antigens that all humans make, even prior to any known exposure to xenogeneic tissues (natural antibodies).
Acute rejection occurs mostly in the first few days or weeks after transplantation. Up to 70% of graft recipients experience one or more acute rejection episodes. When taking place in the first few days after grafting, it may correspond to a secondary (second set) immune response, implying that the patient had been previously sensitized to the HLA antigens pre-sent in the organ donor (as a consequence of a previous transplant, pregnancy, or blood transfusions). When occurring past the first week after grafting, it usually corresponds to a primary (first set) response.
Acute rejection is predominantly mediated by T lymphocytes, and controversy has arisen concerning the relative importance of CD8+cytotoxic lymphocytes vs. helper CD4+ lymphocytes. Most likely, both subsets play important roles.
In rejected organs, the cellular infiltrates contain mostly monocytes and T lympho-cytes of both helper and cytotoxic phenotypes and lesser frequencies of B lymphocytes, NK cells, neutrophils, and eosinophils. All these cells have the potential to play significant roles in the rejection process. CD4+ helper T lymphocytes are believed to play the key role, be-cause of their release of cytokines involved in cell-mediated inflammatory reactions. Inter-leukin-2 and IL-4 promote the expansion of CD8+ lymphocytes and B cells, interferon-enhances the expression of MHC class II antigens in the graft, and chemotactic inter-leukins, such as IL-8 (also released by activated monocytes and macrophages), attract lym-phocytes and granulocytes to the transplanted organ.
In most cases acute rejection, if detected early, can be reversed by increasing the dose of immunosuppressive agents or by briefly administering additional immunosuppressants. However, this simple approach is complicated by the uncertainties that often surround the diagnosis of rejection.
The initial diagnosis of acute rejection is usually based on clinical suspicion. Abnor-mal laboratory studies or functional deterioration of the grafted organ are the main bases for considering the diagnosis of acute rejection. Confirmation usually requires a biopsy of the grafted organ. There are established histological criteria for the identification of an acute rejection reaction in transplanted organs. A hallmark finding in graft undergoing acute rejection is a heavy mononuclear cell infiltration of the affected organ or tissue. The predominance of mononuclear cells indicates that acute rejection falls into the general cat-egory of delayed hypersensitivity reactions.
Since biopsy is an invasive procedure with potential complications and pitfalls, sev-eral approaches to the noninvasive diagnosis of rejection have been attempted. Particular attention has been directed to the measurement of cytokines and other substances released by activated T lymphocytes, such as IL-2, in serum and in urine (in the case of renal trans-plants). However, these tests have been found to be lacking in sensitivity and specificity.
This type of rejection is characterized by an insidiously progressive loss of function of the grafted organ. Recent data show a positive correlation between the number of HLA in-compatibilities and the progression of chronic rejection, which is difficult to control by any type of therapy.
It is not certain if chronic rejection is a unique process or if it represents the final com-mon pathway of multiple injuries occurring over a protracted period of time, including acute rejection episodes, infection, and atherosclerosis. Actually, the functional deterioration as-sociated with chronic rejection seems to be due to both immune and nonimmune processes.
The immune component of chronic rejection is believed to cause vascular endothe-lial injury. A variety of cells, such as granulocytes, monocytes, and platelets have an in-creased tendency to adhere to injured vascular endothelium. The expression of PAF on the membrane of endothelial cells may be one of the major factors determining the adherence of neutrophils and platelets, both types of cells having PAF receptors on their membranes. On the other hand, a variety of interleukins and soluble factors are released by activated leukocytes at the level of the damaged vessel walls, including IL-1 and platelet-derived growth factor (PDGF). A layer of platelets and fibrin covers the damaged endothelium, while proliferating fibroblasts and smooth muscle cells can be found in the subendothelial space. The end result is a proliferative lesion in the vessels as a consequence of the in-flammatory nature of the process, which progresses towards fibrosis and occlusion.
A 45-year-old white male with glomerulonephritis underwent a cadaveric renal transplant. The renal allograft was functional within 24 hours of transplantation, and over the next 3 postoperative days the patient’s creatinine dropped from 10.2 to 1.7 mg/dL. The patient re-cuperated from the operation well and was discharged from the hospital on the 5th post-operative day. He returned to the hospital 4 days later complaining of fever, malaise, de-creased urine output, weight gain, and increased blood pressure. Laboratory investigation revealed a creatinine that had risen to 3.2 mg/dL. Percutaneous renal biopsy was obtained and pathological examination of the tissue revealed a prominent interstitial lymphocytic in-filtrate with tubular necrosis. The patient was treated with high-dose intravenous gluco-corticoids for 3 days. During this time the fever abated, urine output rose, and creatinine decreased to 2.2. The patient was discharged in good clinical condition with stable and ac-ceptable renal function. He continued to do well with maintenance doses of prednisone, mycophenolic acid, and cyclosporine until approximately 8 weeks after transplant, when he presented with fevers, malaise, diffuse abdominal pain, bloody stools, and shortness of breath. Chest x-ray revealed a fine reticular interstitial infiltrate of the lungs, and blood gas analysis showed hypoxia while breathing room air. Physical examination revealed rhonchi and diminished transmission of breath sounds on both sides of the thorax, more ac-centuated on the bases, minimal hepatosplenomegaly, and a diffusely tender abdomen. Oc-cult blood was detected in the stools.
What was the most likely cause of functional deterioration soon after the transplant? Were the symptoms 8 weeks after the transplant related to the same process that af- fected the patient 6 weeks earlier?
Should any tests be ordered to clarify the patient’s later complaints? What therapeutic options would you consider?