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CASE 33


A 22-year-old man is admitted to the intensive care unit (ICU) in severe respiratory distress. This unfortunate fellow was diagnosed with chronic myelogenous leukemia (CML) 6 months ago. His doctors advised both him and his family that a bone marrow transplant offered the only chance of cure. Extensive searching of relatives who were prepared to donate marrow failed to find a good match. However, searching the bone marrow transplant registry revealed one donor matched for all class I and II disparities. Transplant was performed 5 months earlier, after pretreatment with cyclophosphamide. He has had three episodes of graft-versus-host disease (GvHD), all of which resolved with pulses of anti-CD3 antibodies and corticosteroids. His current medications include cyclosporine, methotrexate, and prednisone. He has had hematuria for 10 days and watery diarrhea for 5. While in the ICU his respiratory distress worsens and there is an urgent intubation to allow for adequate oxygenation. All cultures are negative. At this stage you are not sure of what might be going on but are aware of a number of possibilities.



QUESTIONS FOR GROUP DISCUSSION



1. Explain why it is technically more difficult to closely match a solid organ compared with matching for bone marrow transplant.

2. Matching is generally done using restriction fragment length polymorphism (RFLP) or allele-specific polymerase chain reaction (PCR) to match for MHC antigens. Despite this, vigorous rejection may occur. Explain.

3. It is of interest that in the early years of clinical transplantation, concern was voiced that from our knowledge of how the T cell immune system developed one might predict that bone marrow transplant recipients might become immunologic cripples.

4. T cells expressing T cell receptors that can interact with self MHC (on thymic epithelium) with appropriate avidity are positively selected to leave the thymus. How do you reconcile the fact that in a bone marrow transplant, the antigen-presenting cells in the periphery would express donor MHC, yet the donor T cells have been educated on host thymic epithelial cells expressing host MHC (that is, how do T cells recognize these antigen complexes?)?

5. Patients who receive bone marrow transplants must receive immunosuppressive therapy to reduce the risk of HvGD and GvHD (host versus graft disease; graft versus host disease). To what type of infections are these patients particularly prone? How might these present?

6. GvHD itself presents often as a multisystemic disease with gastrointestinal, lung, genitourinary, and skin involvement. However, an alternative cause of these complaints could be that the patient has an infection (see question 5). Why is it important to rule out infection as the cause of these symptoms?

7. Why is it very important that you do not ignore GvHD as an unlikely cause of the symptoms while you investigate a possible viral infection? Discuss how you would proceed to “cover” both possibilities.

8. Within 2 days, the patient died of multiple organ failure. Blood culture showed gram-negative sepsis and disseminated cytomegalovirus (CMV) infection. CMV (human herpesvirus 6) has evolved strategies by which to hinder the immune response. Discuss these strategies.

9. With reference to question 8, one would expect that a decrease in class I MHC expression would hinder CD8+ T cells but a decrease in class I MHC should lead to NK cell activation. What cytokines are required to enhance NK cell cytotoxicity? What cell secretes these cytokines?

10. What cell population is the target of anti-CD3 therapy? Of cyclosporine therapy?


RECOMMENDED APPROACH



Implications/Analysis of Family History

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Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on 33

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