- Types of Transplantation:
- Autografts - tissue is transplanted from one part of the body to another, in the same person. An example of this is skin grafting of intact skin to an area of a burn injury. An autologous bone marrow stem cell transplant is another example.
- Allografts - tissue is transplanted from the same species, from one human to another. This is the common method of transplantation for most organs such as kidney, heart, liver, and lung. Blood transfusion is another form of allograft, albeit temporary due to the finite lifespan of the transfused cells.
- Xenografts - tissue is transplanted from one species to another. The most common example is the use of pig heart valves to replace a damaged human heart valve. Whole organ transplants using this methodology are rare and controversial.
- Tissue Typing:
- In order for many transplants to be successful, there must be HLA tissue typing. There is the potential for a total of 12 separate HLA loci, 6 class I MHC loci (A, B, and C), and 6 class II MHC loci (DR, DQ, and DP). In reality, only 6 of these have major importance-the alleles for A, B, and DR.
- Non-MHC proteins (so-called "minor histocompatibility" antigens) can be important in some circumstances. The antigens expressed on the surface of red blood cells different among persons. The best known antigens are A and B glycoproteins that determine the four blood types: A, B, AB, and O (lacking A and B). Antigen matching must be done for transfusion of blood products.
- HLA antigens are not always expressed uniformly throughout all tissues to the same degree. Organs such as heart and liver are much less likely to be subject to rejection than are kidney and marrow transplants. Heart and liver may contain fewer antigen presenting cells (APCs) that aid in immune activation. Thus, the determinants for heart and liver transplantation are availability and size. HLA antigens are poorly expressed in the placenta-a fetal organ-in order to keep the fetus from being "rejected" in utero.
- Immunosuppressive Therapy:
- The major breakthrough in transplantation came from the discovery that cyclosporine was effective in ameliorating rejection. Cyclosporine was originally discovered as a natural product of a Norwegian mountain fungus. Cyclosporine binds to calcineurin, a phosphatase which is activated by calmodulin which binds calcium in the process of tyrosine kinase signalling from CD3 receptor of the T cell surface. This inhibits cytokine production and blunts the immune response. Other immunosuppressants include FK 506, a macrolide antibiotic which inhibits T cells, and corticosteroids, which blunt inflammatory reactions by depleting lymphocytes.
- In order to avoid rejection phenomena, one focus of research has centered on the use of fetal cells, particularly fetal stem cells. Fetal cells are, immunologically speaking, uncommitted and will not, theoretically, be subject to rejection. This field of research is controversial because of differing opinions and beliefs regarding the nature and use of fetal tissues. Science has advanced beyond society's ability to cope with the issues. Ethical dilemmas result from research proposals. Scientists usually want to move ahead and leave the societal consequences for others to solve. Governments, converserly, are unwieldy bureaucracies that have difficulty dealing with any issues in a timely fashion. In a democratic, pluralistic society such as ours in the U.S., we try to pick policies that will please as many people as possible and offend as few as possible. Such policies tend not to be ideal for anyone.
- Transplant Rejection
- There are many forms of transplant rejection, and many are defined in terms of the organ involved. Criteria have been established to determine the presence and nature of rejection in order to try and treat it. The classic models of rejection come from renal transplantation, one of the most common forms of organ transplantation. Thre are three major forms of renal transplant rejection:
- Hyperacute - preformed antibodies to the transplant are circulating in the recipient and immediately attack the donor kidney, causing acute vascular injury within minutes. This rejection reaction is virtually never seen because tissue typing is performed prior to transplantation to match donor and recipient.
- Acute - this rejection reaction can occur within days or months, or sometimes even years, after transplantation. It is based upon cell-mediated immune reactions. Recipient T lymphocytes are directed against the graft, either the parenchyma (cellular rejection) or the vessels (vascular rejection). Antibodies are typically present with the vascular form of rejection, which is harder to treat with immunosuppressive drugs.
- Chronic - this can occur months to years after transplantation and is directed at vessels, which become increasingly fibrotic and narrowed, leading to ischemic injury. The fibrosis is the result of cytokine secretion by T cells. This form of rejection is very hard to treat.
- Case Presentation: Chronic rejection
- History: A 58 year old man has a history of diabetes mellitus type 2. He has had worsening renal function for the past 5 years. His creatinine clearance was 5 mL/min. He received a cadaveric renal transplant. Following the surgery, he did well for 6 months, but then had worsening renal function, with a rising urea nitrogen and creatinine. Radiographic imaging (renal scintigraphy) revealed diminished blood flow with decreased uptake and excretion of contrast material of the transplanted kidney. A urinalysis shows 1+ protein, 1+ glucose, and no red cells or white cells. Urine microscopic examination shows a few calcium oxalate crystals. His immunosuppressive therapy is increased, but his renal function continues to deteriorate.
- What is a renal biospy most likely to show?
- The biopsy will probably show vascular fibrosis with scattered lymphocytes in the vascular media, with intact renal glomeruli and tubules, without significant interstitial inflammation. These are findings of chronic rejection.
Renal Arteries with Chronic Vascular Rejection
- What is the prognosis?
- Poor. Cases of chronic rejection respond poorly to any therapy. The patient will have to go on dialysis until a new kidney can be found.
- Case Presentation: Acute rejection
- History: A 41 year old woman has had worsening renal function for the past two years. She goes on hemodialysis therapy for two years. A transplant kidney is found (from a person who died in an auto accident). She initially does well for the first three months following the transplant procedure. Her immunosuppressive regimen consists of cyclosporine, prednisolone, and azathioprine. She then develops a mild fever for several days, with reduced urine output. Her serum urea nitrogen and creatinine are noted to be increased. A urinalysis shows 1+ protein and 1+ blood with no glucose or ketones. A urine microscopic examination reveals the presence of white blood cells (both neutrophils and lymphocytes) and red blood cells.
- What is a renal biospy most likely to show?
- The biopsy will probably show an active tubulitis with mixed inflammatory infiltrates. The renal tubules will be infiltrated by lymphocytes, plasma cells, macrophages, and neutrophils and will show some necrosis. There will be an interstitial mononuclear inflammatory infiltrate with edema and hemorrhage. These are findings of acute cellular rejection.
Acute Cellular Rejection
- What should be done?
- Her immunosuppressive therapy, particularly with corticosteroids, will be increased. Once this is done, her renal function improves.
- What is the prognosis?
- Acute cellular rejection episodes typically respond to therapy. However, this does not guarantee that she will not have additional episodes of acute rejection, or that she may develop chronic rejection.
- Case Presentation: Graft versus host disease
- History: A 27 year old woman has had worsening fatigue and more frequent and severe infectious disease episodes in the past 6 months. She is found to have a CBC that shows:
-
| Hgb |
8.8 g/dL |
| Hct |
26.5% |
| MCV |
97 fL |
| Platelet ct |
22,000/microliter |
| WBC count |
2,150/microliter |
| WBC diff |
10 segs, 5 bands, 1 metamyelocyte, 69 lymphs, 15 monos |
- A bone marrow biopsy shows about 10% cellularity, with reduction in all major cell lines. No blasts are noted.
- She receives a peripheral blood stem cell transplant from an unrelated donor, with a 5/6 antigen match (1 HLA antigen mismatch). She has engraftment by post-transplant day 10, with increasing WBC, RBC, and platelet counts. However, 2 weeks later she develops a mild maculopapular rash that becomes desquamative involving her extremities. She has erythema of her palms. She also has a mild watery diarrhea of relatively low volume (5 to 8 stools per day). Her sclerae are noted to be mildly icteric. She receives therapy with methotrexate, cyclosporine, and corticosteroids, and these problems resolve.
- However, 6 months later she develops areas of redness on her oral mucosa, and some of these areas become ulcerative, making it difficult for her to eat. She has erythematous plaque-like areas involving the skin of ears, palms, and soles. Over time, these areas become indurated shiny whitish plaques. She has increasing respiratory distress with dyspnea with persistent cough, expiratory wheezes, inspiratory rales, and hyperinflation on chest radiograph without infiltrates. A transbronchial biopsy of the lung shows bronchiolitis obliterans. She is treated with cyclosporine and corticosteroids, but her pulmonary function does not improve.
- What complication did she initially develop?
- She had acute graft versus host disease. The tissues primarily affected by acute GVHD are skin, liver, and GI tract. Persons with acute GVHD may manifest with skin rash, liver failure (jaundice), and/or diarrhea.
- What complication did she develop 6 months following the transplant?
- She had chronic graft versus host disease. This condition can resemble an autoimmune disease. Skin and oral changes are very common. Pulmonary involvement with development of bronchiolitis obliterans can be life-threatening.
- Explain the pathophysiology of these complications.
- Persons who receive bone marrow transplants are obtaining stem cells from the donor which prolierate to repopulate the recipient marrow and lymphoid organs with hematopoietic and immune cells. The donor lymphocytes may recognize the recipient tissues as foreign and become activated to produce an immune response. Thus, the graft attacks the host. GVHD is prevented or lessened by prior HLA matching.
- In acute GVHD, the T lymphocytes of the donor become active, particularly with cytokine stimulation from other inflammatory processes. These T cells attack host tissues and induce apoptosis directly and produce damage indirectly from inflammatory responses. Some degree of acute GVHD occurs in about half of BMT patients. Most cases are mild.
"Apoptosis" or Single Cell Necrosis
- In chronic GVHD, the disease acts more like an autoimmune or immunodeficient state. There is a predominantly TH-2 immune response. The major risk factor for chronic GVHD is a prior episode of acute GVHD. Fewer BMT patients develop this chronic form of GVHD, but it is much harder to treat.
- Transfusion associated graft versus host disease
- There is another form of GVHD that is seen rarely with transfusion of blood products that contain lymphocytes. This is known as transfusion-associated GVHD (TAGVHD) and it is a different disease from that seen in marrow transplants. TAGVHD is a uniformly fatal complication. It is more likely to occur when blood products are transfused from close relatives (similar HLA types, but not the same). Donor lymphocytes will not be rejected if the recipient shares some HLA types, but the donor lymphocytes will attack recipient tissues that do not share donor HLA antigens, a so-called "one way" mismatch. In order to prevent this disease, the blood products must be irradiated to kill the lymphocytes prior to transfusion. Japan has the highest incidence of TAGVHD because it is the most racially homogenous population on earth.
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