Case 43

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 43

Ms. Bell received cardiac transplantation approximately 6 years earlier for a cardiomyopathy that developed after she received chemotherapy (doxorubicin [Adriamycin]) for breast cancer. She has had routine endomyocardial biopsies each year, the last being 1 year ago. At that time the pathologist read the biopsy as normal, with no signs of rejection. The only change in her anti-rejection therapy over the past 2 years was a reduction in the prednisone dose (now 7.5 mg/day) and replacement of cyclosporine (which she had received for nearly 5 years since the time of transplantation) with tacrolimus. You (her son) were told that the advantage of tacrolimus was a slightly improved toxicity profile. You arrived home for a visit this afternoon to find your mother confused and with a droop on the left side of her face/mouth. You immediately call an ambulance and arrange transport to the local hospital.

QUESTIONS FOR GROUP DISCUSSION

1. Tissue rejection is of concern for any transplant patient. Explain why this patient’s symptoms are unlikely to be caused by hyperacute rejection.
2. Review the immunology of acute rejection and why this is unlikely the cause of the clinical presentation. In general terms how is acute rejection treated? Provide a rationale for the use of each of the following as therapy for acute rejection: (a) intravenous anti-CD3 antibodies and (b) anti-CD25 antibodies.
3. Explain how you would determine whether the clinical symptoms are the result of tissue (heart) damage.
4. Chronic rejection is still a possibility. What is the underlying cause of chronic rejection? Describe how (a) numerous, but minor, acute rejection episodes and (b) chronic immunostimulation against minor antigens in the graft could lead to chronic rejection. Discuss how this would affect heart function and how it might lead to generalized neurologic deficits. What aspect of this patient’s clinical presentation cannot be explained by a diagnosis of chronic rejection?
5. A diagnosis of “rejection” seems unlikely in this patient as discussed in the previous questions. What three potential problems should we consider given that this patient is on immunosuppressive therapy?
6. Discuss the three types of malignancies to which this patient may be susceptible and how these could account for the neurologic symptoms.
7. Why would you want to include Ms. Bell’s original breast cancer as a risk, in addition to the three that you have just described? What is the proposed mechanism underlying this increased risk of malignancies?
8. How would you rule out a new immune response in a patient known to be (a) infected with a virus prior to the transplant and (b) uninfected before the transplant?
9. Direct drug toxicity reactions are also a major consideration. Discuss how toxicity reactions secondary to therapy with tacrolimus and cyclosporine would manifest in (a) the kidney and (b) nervous tissue?
10. Discuss the possible complications of prednisone therapy. Explain how this would account for this patient’s clinical symptoms.

RECOMMENDED APPROACH

Implications/Analysis of Family History

At this stage we are not provided with any family history. Family history regarding cardiac problems is likely irrelevant in that Ms. Bell’s heart problems were related to chemotherapy after she was diagnosed with breast cancer.

Implications/Analysis of Clinical History

Ms. Bell received a cardiac transplant 6 years ago, and all the evidence we are provided with indicates that this was a successful graft in that the yearly endomyocardial biopsies have all been normal. In fact, the only change in her anti-rejection therapy has been a reduction in immunosuppressive therapy and change from cyclosporine to tacrolimus, which is slightly less toxic.

Chronic Rejection

Chronic rejection, most readily correlated with release of nonspecific “growth factor”-like mediators (e.g., fibroblast growth factor, endothelial growth factor) tends to take the form of an insidious fibrosing/proliferative reaction, which is relatively refractory to immunosuppressive treatment. (Fibrosis refers to the excessive accumulation of connective tissue in an organ.) Note that a fibrotic (noncompliant) heart would not pump as efficiently. Therefore, the resulting inability to oxygenate the tissues might cause some generalized neurologic deficits (e.g., the confusion referred to in the case description). Thus, one might consider the neurologic deficits as one possible manifestation of chronic rejection. However, the history suggests a more sudden onset, which does not fit this picture.

Organ-Specific Damage

Organ-specific damage is high on the list of possible diagnoses. Whenever we look for organ-specific damage (from T cell-mediated “attack”) we think of organ-specific “markers” for the damage. Thus, in kidney grafts, you would measure creatinine. For the heart you can look at the electrocardiogram and also measure specific cardiac muscle enzymes in the blood (see Implications/Analysis of Laboratory Investigation).

Implications/Analysis of Laboratory Investigation

Routine blood work, physical examination, electrocardiogram, and serum levels of cardiac enzymes should be initiated at this time. A number of cardiac enzymes (e.g., troponin I, creatine phosphokinase, creatine kinase) are released when heart tissue is damaged. Although an increase in the level of these enzymes occurs after heart damage, some of these enzymes are present in other tissues, as well. Therefore, results of these tests must be interpreted in light of the electrocardiographic findings. Measurement of cardiac muscle enzymes was normal, as was the ECG, ruling out killing (lysis) of heart cells as the cause of this patient’s problem.

Side Effects of Drug Therapy

You must consider the fact that this disorder could represent one of a possible number of side effects of the treatment she received for the transplant. In general, the chronically immunosuppressed populations show an increased frequency of three major problems: (1) malignancy, (2) infections, and (3) drug toxicity.

Additional Laboratory Tests

Impaired tumor immunosurveillance, as a result of the immunosuppression she has received, could make this patient more susceptible to a secondary metastasis (to the brain) from her original breast cancer. A new-onset central nervous system (CNS) lymphoma might also be a concern. Both lesions might cause confusion, as might a viral encephalopathy.

To address these concerns, computed tomography (CT) was requested along with viral antibody titers for herpes simplex virus (human herpesviruses 1 and 2) and cytomegalovirus (human herpesvirus 6). CT was normal and the viral antibody titers were negative, ruling out both a CNS lymphoma and viral encephalopathy.

Having ruled out graft rejection, infection, and a CNS lymphoma we need to consider drug toxicity as the cause of this patient’s clinical presentation.

DIAGNOSIS

Toxicity, directly and indirectly from the drugs themselves, can cause severe complications. The drugs she is receiving as part of the post-transplant immunoprophylaxis, tacrolimus (and indeed the cyclosporine she received earlier) are nephrotoxic (damage the kidney) and have also been reported to show toxicity to nervous tissues (neurotoxic). Most of the neurotoxicity reported tends to reflect damage to peripheral nerves (peripheral neuropathy) rather than to reflect toxicity within the CNS.

Prednisone has been shown to leave patients at increased risk of atherosclerotic disease, both within the vessels of the grafted organs (here, the heart) and elsewhere in the body (e.g., the brain). This narrowing of the blood vessels, in turn, results in increased risk of ischemic damage to the central organs (heart attack and, in the brain, a stroke). Most of the evidence points to prednisone toxicity as causing narrowing of the blood vessels, which, in turn, led to ischemic damage in the brain. This manifested as a stroke.

THERAPY

Treatment of stroke has been revolutionized in the past few years. Now instead of reliance on anti-thrombotic drugs such as aspirin (or the newer clopidogrel [Plavix]), there is intense interest in the acute use of “clot dissolving therapy” (tissue plasminogen activator therapy) such as that used for heart attacks and stroke. This is not without considerable risk (increased risk of bleeding with intracerebral hemorrhage and death), so risk-benefit considerations are crucial.

ETIOLOGY: TRANSPLANTATION COMPLICATIONS

Graft rejection, infections, malignancies, and drug toxicity are all possible complications after transplantation and immunosuppressive therapy

Graft Rejection

For the most part, grafts are allografts. That is, they are donated from another person who is genetically dissimilar. The rejection of an allograft reflects a composite of both antigen-specific and antigen-nonspecific inflammatory processes that include activation of (1) the intrinsic coagulation pathway; (2) T cells and B cells; and (3) macrophages, neutrophils, mast cells/ basophils, and the vascular endothelium. Cytokines, chemokines, and inflammatory products secreted by antigen-specific and antigen-nonspecific cells all contribute to graft rejection.

Hyperacute Rejection

Hyperacute rejection, as the name implies, occurs in the immediate aftermath of transplantation—it is antibody (and complement) mediated. When hyperacute rejection occurs after an allograft, it is an indication that the recipient has previously been sensitized to the antigens on the donor tissue and these antibodies were not detected before the transplant. This could happen when the recipient is a multiparous woman or is receiving a transplant after a previous graft failure.

Acute Rejection

Acute rejection is a function of, among other things, the degree of MHC incompatibility between donor and host and is minimized both by “matching” of donor and recipient at the MHC before engraftment and by judicious use of immunosuppressive drug therapy after engraftment to decrease the likelihood of sensitization. Despite immunosuppressive therapy, some degree of cell activation can (and generally does) occur, marked both by development of killer CD8+ T cells (CTLs) specific for graft antigen/MHC and by activated CD4+ cells, able to release a variety of molecules capable of engaging other elements of the immune recognition process.

ROLE OF CD4+ T CELLS

Activation of CD4+ T cells during acute graft rejection occurs after both direct and indirect recognition of allo-MHC. In direct recognition, donor peptides are displayed within the groove of MHC molecules on the surface of host antigen-presenting cells. That is, T cells are recognizing self-MHC/donor peptide complexes. The number of T cells responding to this form of antigen recognition is comparable to that of other T cell responses against nominal antigen. In contrast, direct allorecognition of donor MHC molecules (donor MHC) expressed on donor cells leads to the activation of large numbers of T cells and vigorous immune response against the donor tissue.

Activated CD4+ cells release both interleukin (IL)-2 (a T cell growth factor) as well as interferon gamma (IFNγ) and tumor necrosis factor (TNF), both potent inflammatory mediators, which can trigger activation of cells of the innate immune system (e.g., macrophages/neutrophils) to cause damage. Although CD4+ cells both augment differentiation of CD8+ killer T cells and provide “help” for B cell recognition (and conventional immunoglobulin production in response to foreign antigen), antibody-mediated damage itself is generally not thought to contribute in an important fashion to early graft alloreactions and loss.

ROLE OF SOLUBLE MEDIATORS AND NONSPECIFIC IMMUNE CELLS

Chemokines, produced by a number of cells in the inflammatory milieu (including fibroblasts/endothelial cells) attract other cells to the site of rejection, further propagating the process. Along with endothelial cell activation, engagement of the serum-derived plasminogen and thrombotic cascade occurs, as well as thrombosis mediated both by tissue factor and a novel prothrombinase discovered comparatively recently and referred to as fibroleukin. This procoagulant activity (a product of endothelial cells and macrophages) is distinct from previously described ones and occurs after immune-mediated activation of an inflammatory event.

REGULATORY T CELLS

Several types of immune cells have been shown to downregulate T cells that play a role in acute graft rejection. Of these, the CD4+, CD25+ regulatory T cells (Treg) have been most widely studied. Treg cells have been shown to inhibit CTL proliferation, cytokine production, and B cell activation. Furthermore, Treg cells appear to induce phenotypic change in some cytopathic cells such that they become IL-10–secreting T cells. IL-10 downregulates IL-12 secretion by antigen-presenting cells. IL-12 plays a key role in the differentiation of immature CD4+ T cells to mature T cell–secreting proinflammatory type 1 cytokines. The role that these IL-10-secreting cells play in immunoregulation of transplants is underscored by the fact that (in in vitro systems) neutralization of IL-10 abrogates its immunosuppressive effect on acute rejection during skin grafts. In allograft rejection, it seems that the contribution of Treg cells, while present, is overwhelmed by the vigorous immune response generated by direct alloantigen recognition by T cells.

THERAPY FOR ACUTE REJECTION

Acute rejection is mediated primarily by T cells, and so these cells are the target of immunosuppressive therapy. This would be done only after consultation with the transplant team and would almost certainly necessitate obtaining a biopsy (to document evidence for rejection). Medication that would likely be used in such a scenario would include intravenous OKT3 (anti-CD3 antibodies, directed at all T cells) and/or anti-CD25 antibodies (directed at activated T cells expressing IL-2 receptor as a marker of their activation/proliferation).

Chronic Rejection

Chronic rejection may reflect the net outcome of numerous (even unidentified) minor acute rejection episodes and/or a chronic immunostimulation directed against minor incompatibilities (minor antigens) between graft and recipient. Like acute rejection, chronic rejection involves components of cell-mediated immunity; however, chronic rejection also involves the dramatic increase in non–T cell–derived growth factors (e.g., fibroblast growth factor), which leads to the production of fibrosed tissue that does not function well (Fig. 43-1). Note, too, that chronic rejection is generally not easily treated.

image

FIGURE 43-1 Histopathology of different forms of graft rejection. A, Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration of a glomerulus. B, Acute rejection of a kidney with inflammatory cells in the interstitium and between epithelial cells of the tubules. C, Acute rejection of a kidney allograft with inflammatory reaction destroying the endothelium of an artery. D, Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima.

(Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston.)

Infections

Complications of the immunosuppressive therapy used to ensure graft survival are unfortunately quite common. An increased incidence of (opportunistic) infection is observed in these patients. Recrudescence of earlier infections that were previously cleared can also cause problems.

Individuals who are immunosuppressed are particularly prone to viral infections. This likely represents a consequence of suppressed CD4/CD8-mediated T cell immunity. In general, immunoglobulin levels, essential for resistance to bacterial infection, are unaffected.

When infection is suspected, determination of antibody titers for the suspect infection should include assays for both IgM and IgG. IgM antibodies would indicate a new immune response in a person known to be seronegative before transplantation. IgG antibodies would indicate a previous infection.

Malignancy

An increased evidence of malignancy is a risk factor for transplant patients. It is worth noting that although they are immunosuppressed, this patient population (the transplant population) does not seem to be at risk for increases in all solid tumors but predominantly those of viral etiology, lymphomas, and skin tumors (especially epithelial cancers). This is thought to indicate a risk involvement caused by direct action of drugs on the immune system and/or specific body tissues, rather than an indirect effect on immunosurveillance itself.

Toxicity

Toxicity, directly and indirectly from the drugs themselves, can cause severe complications. Tacrolimus (and indeed cyclosporine) can damage the kidney (nephrotoxic) and have also been reported to show toxicity to nervous tissues (neurotoxic). Most of the neurotoxicity reported tends to reflect damage to peripheral nerves (peripheral neuropathy) rather than to reflect CNS toxicity. Reactions are important side effects to consider.

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