Case Studies in Immunology: Graft-Versus-Host Disease: a Clinical Companion [1st edition] 9781136981937, 0815341458, 9780815341451, 0203853318, 1136981934

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Graft-Versus-Host Disease

• Harvard Medical School

This edition published in the Taylor & Francis e-Library, 2009. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk. Vice President: Denise Schanck Senior Editor: Janet Foltin Text Editor: Eleanor Lawrence Assistant Editor: Sigrid Masson Editorial Assistant: Katherine Ghezzi Senior Production Editor: Simon Hill Copyeditor: Bruce Goatly Indexer: Merrall-Ross International Ltd. Illustration: Blink Studio Layout: Georgina Lucas © 2008 by Garland Science, Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Every attempt has been made to source the figures accurately. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. No part of this book covered by the copyright herein may be reproduced or used in any format in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the publisher. 10-digit ISBN 0-8153-4145-8 (paperback) 13-digit ISBN 978-0-8153-4145-1 (paperback)

Library of Congress Cataloging-in-Publication Data Geha, Raif S. Case studies in immunology : a clinical companion / Raif Geha, Fred Rosen. -- 5th ed. p. ; cm. Rosen's name appears first on the earlier edition. Includes index. ISBN 978-0-8153-4145-1 1. Clinical immunology--Case studies. I. Rosen, Fred S. II. Title. [DNLM: 1. Immune System Diseases--Case Reports. 2. Allergy and Immunology-Case Reports. 3. Immunity--genetics--Case Reports. WD 300 G311c 2007] RC582.R67 2007 616.07'9--dc22 2007002977

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Preface

The science of immunology started as a case study. On May 15, 1796 Edward Jenner inoculated a neighbor’s son, James Phipps, with vaccinia (cowpox) virus. Six weeks later, on July 1, 1796, Jenner challenged the boy with live smallpox and found that he was protected against this infection. During its 208 year history the basic science of immunology has been closely related to clinical observations and has shed light on the pathogenesis of disease. The study of immunology provides a rare opportunity in medicine to relate the findings of basic scientific investigations to clinical problems. The case histories in this book are chosen for two purposes: to illustrate in a clinical context essential points about the mechanisms of immunity; and to describe and explain some of the immunological problems often seen in the clinic. For this fifth edition, we have added five completely new cases that illustrate both recently discovered genetic immunodeficiencies and some more familiar and common diseases with interesting immunology. We have revised other cases to add newly acquired information about these diseases. Fundamental mechanisms of immunity are illustrated by cases of genetic defects in the immune system, immune complex diseases, immune mediated hypersensitivity reactions and autoimmune and alloimmune diseases. These cases describe real events from case histories, largely but not solely drawn from the records of the Boston Children’s Hospital and the Brigham and Women’s Hospital. Names, places, and time have been altered to obscure the identity of the patients described; all other details are faithfully reproduced. The cases are intended to help medical students and pre-medical students to learn and understand the importance of basic immunological mechanisms, and particularly to serve as a review aid; but we hope and believe they will be useful and interesting to any student of immunology. Each case is presented in the same format. The case history is preceded by basic scientific facts that are needed to understand the case history. The case history is followed by a brief summary of the disease under study. Finally there are several questions and discussion points that highlight the lessons learned from the case. These are not intended to be a quiz but rather to shed further light on the details of the case. The Garland Science website (www.garlandscience.com) now provides instructors who adopt Case Studies with a link to Garland Science Classwire, where the textbook art can be found in a downloadable, web-ready format, as well as in PowerPoint-ready format. We are grateful to Dr. Peter Densen of the University of Iowa for C8 deficiency case material, Dr. Sanjiv Chopra of Harvard Medical School for the case on mixed essential cryoglobulinemia and Dr. Peter Schur of the Brigham and Women’s Hospital for the rheumatoid arthritis case. We also thank Dr. Jane Newburger of the Boston Children’s Hospital for the case on rheumatic fever and Dr. Eric Rosenberg of the Massachusetts General Hospital for the AIDS case. We are also greatly indebted to our colleagues Drs. David Dawson, Susan Berman, Lawrence Shulman and David Hafler of the Brigham and Women’s Hospital, to Dr. Razzaque Ahmed of the Harvard School of Dental Medicine, to Drs. Ernesto Gonzalez and Scott Snapper of the Massachusetts General Hospital and to Drs. Peter Newburger and Jamie Ferrara of the Departments of Pediatrics of the University of Massachusetts and the University of Michigan and Dr. Robertson Parkman of the Los Angeles Children’s Hospital as well as Henri de la Salle of the Centre régional de Transfusion sanguine in Strasbourg and Professor Michael

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Levin of St. Mary’s Hospital, London for supplying case materials. Our colleagues in the Immunology Division of the Children’s Hospital have provided invaluable service by extracting summaries of long and complicated case histories; we are particularly indebted to Drs. Lynda Schneider, Leonard Bacharier, Francisco Antonio Bonilla, Hans Oettgen, Jonathan Spergel, Rima Rachid, Scott Turvey, Jordan Orange, Eamanuela Castigli, Andrew McGinnitie, Marybeth Son, Melissa Hazen, Douglas McDonald and John Lee, and to Lilit Garibyan, third year medical student at Harvard Medical School, in constructing several case histories. In the course of developing these cases, we have been indebted for expert and pedagogic advice to Fred Alt, Mark Anderson, John Atkinson, Hugh Auchincloss, Stephen Baird, Zuhair K. Ballas, Leslie Berg, Corrado Betterle, Kurt Bloch, Jean-Laurent Casanova, John J. Cohen, Michael I. Colston, Anthony DeFranco, Peter Densen, Ten Feizi, Alain Fischer, Christopher Goodnow, Edward Kaplan, George Miller, Luigi Notarangelo, Peter Parham, Jaakko Perheentupa, Jennifer Puck, Westley Reeves, Patrick Revy, Peter Schur, Anthony Segal, Lisa Steiner, Stuart Tangye, Cox Terhorst, Emil Unanue, André Veillette, Jan Vilcek, Mark Walport, Fenella Woznarowska, and John Zabriskie. Eleanor Lawrence has spent many hours honing the prose as well as the content of the cases and we are grateful to her for this. We would also like to acknowledge the Garland Science team for their work on the fifth edition.

A note to the reader The cases presented in this book have been ordered so that the main topics addressed in each case follow as far as possible the order in which these topics are presented in the seventh edition of Janeway’s Immunobiology by Kenneth Murphy, Paul Travers, and Mark Walport. However, inevitably many of the early cases raise important issues that are not addressed until the later chapters of Immunobiology. To indicate which sections of Immunobiology contain material relevant to each case, we have listed on the first page of each case the topics covered in it. The color code follows the code used for the five main sections of Immunobiology: yellow for the introductory chapter and innate immunity, blue for the section on recognition of antigen, red for the development of lymphocytes, green for the adaptive immune response, purple for the response to infection and clinical topics, and orange for methods.

Dedication This fifth edition is dedicated to Fred Rosen (1935-2005). Fred dedicated his career of more than 50 years to the investigation and care of patients with primary immunodeficiency disease. Above all, he loved to teach and he did so superbly, aided by an encyclopedic knowledge of immunology, an incisive intelligence, an incredible memory, and charisma combined with an aura of authority. Fred had an enormous influence on many generations of both basic and clinical immunologists. This book is his brainchild and his contribution to it will be sorely missed.

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CONTENTS

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12 Case 13 Case 14 Case 15 Case 16 Case 17 Case 18 Case 19 Case 20

Congenital Asplenia Chronic Granulomatous Disease Leukocyte Adhesion Deficiency Hereditary Angioneurotic Edema Factor I Deficiency Deficiency of the C8 Complement Component Hereditary Periodic Fever Syndromes Interleukin 1 Receptor-associated Kinase 4 Deficiency X-linked Hypohydrotic Ectodermal Dysplasia and Immunodeficiency X-linked Agammaglobulinemia X-linked Hyper IgM Syndrome Activation-induced Cytidine Deaminase (AID) Deficiency Common Variable Immunodeficiency X-linked Severe Combined Immunodeficiency Adenosine Deaminase Deficiency Omenn Syndrome MHC Class I Deficiency MHC Class II Deficiency Multiple Myeloma T-Cell Lymphoma

Case 21 Case 22 Case 23 Case 24 Case 25

Interferon-g Receptor Deficiency Wiskott-Aldrich Syndrome X-linked Lymphoproliferative Syndrome Autoimmune Lymphoproliferative Syndrome (ALPS) Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked Disease Toxic Shock Syndrome Acute Infectious Mononucleosis Mixed Essential Cryoglobulinemia Rheumatic Fever Lepromatous Leprosy Acquired Immune Deficiency Syndrome (AIDS)

Case 26 Case 27 Case 28 Case 29 Case 30 Case 31

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Case 32 Case 33 Case 34 Case 35 Case 36 Case 37 Case 38 Case 39 Case 40 Case 41 Case 42 Case 43 Case 44 Case 45 Case 46 Case 47

Acute Systemic Anaphylaxis Allergic Asthma Atopic Dermatitis Drug-Induced Serum Sickness Celiac Disease Contact Sensitivity to Poison Ivy Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Autoimmune Hemolytic Anemia Myasthenia Gravis Pemphigus Vulgaris Rheumatoid Arthritis Systemic Lupus Erythematosus Multiple Sclerosis Hemolytic Disease of the Newborn A Kidney Graft for Complications of Autoimmune Insulin-Dependent Diabetes Mellitus Graft-Versus-Host Disease

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Graft-Versus-Host Disease

Alien T cells react against their new host. Bone marrow transplantation has proved to be useful therapy for some forms of leukemia, bone marrow failure (aplastic anemia), and primary immunodeficiency diseases. More recently, other sources of hematopoietic stem cells, such as peripheral blood stem cells and cord blood, have also been used for these purposes. Bone marrow and most other sources of hematopoietic stem cells contain mature T lymphocytes, which may recognize the tissues of their new host as foreign and cause a severe inflammatory disease in the recipient. This is known as graft-versus-host disease (GVHD) and is characterized by a rash, which often starts on the face (Fig. 47.1), diarrhea, pneumonitis (inflammation in the lung), and liver damage. To achieve successful engraftment of bone marrow and avoid rejection of the transplant by the host, the immune system of the recipient must be destroyed and the recipient rendered immunoincompetent. This is usually accomplished with lethal doses of radiation or injection of radiomimetic drugs such as busulfan. In children who are already immunoincompetent because of a primary immunodeficiency disease, such as severe combined immunodeficiency (see Case 14), this preparative treatment is not needed.

Topics bearing on this case: T-cell recognition of nonself MHC molecules Reactions of T cells against foreign antigens Transplantation Minor histocompatibility antigens Mixed lymphocyte reaction

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Graft-Versus-Host Disease

GVHD occurs not only when there is a mismatch of classical MHC class I or class II molecules, but also in the context of disparities in minor histocompatibility antigens; such minor differences are likely to be present in all donor–recipient pairs other than identical twins, even when HLA-matched. Mature CD4 T cells in the graft that are activated by allogeneic molecules produce a ‘cytokine storm’ that recruits other T cells, macrophages, and natural killer (NK) cells to create the inflammation characteristic of GVHD. Although B cells may also be present in GVHD inflammation, they do not play a significant role in causing or sustaining GVHD.

Fig. 47.1 The rash characteristic of GVHD often starts on the face.

GVHD is arbitrarily called ‘acute’ if it occurs less than 100 days after the transplant, and ‘chronic’ if it develops after 100 days. Chronic GVHD differs from acute GVHD in other respects and is a more severe and intractable problem. The presence of alloreactive T cells in the donor bone marrow is usually detected in routine laboratory testing by the mixed lymphocyte reaction (MLR) (see Fig. 15.3), in which lymphocytes from the potential donor are mixed with irradiated lymphocytes from the potential recipient. If the donor lymphocytes contain alloreactive T cells, these will respond by cell division. Although the MLR is routinely used for the selection of donors it does not accurately quantify alloreactive T cells. Although the limiting-dilution assay more precisely counts the frequency of alloreactive T cells, it is too cumbersome for routine clinical use.

The case of John W. Wells: a curative therapy becomes a problem.

boy with 7-year-onldemia. Order severe a rrow biopsy. bone ma

aplastic ls a e v e r y s Biop Bone marrow anemia. nt. transpla

John was healthy until he was 7 years old, when his mother noticed that he had become very pale. She also noticed small hemorrhages (petechiae) on the skin of his arms and legs and took John to the pediatrician. Apart from the pallor and skin petechiae, a physical examination showed nothing unusual. The pediatrician ordered blood tests, which revealed that John was indeed very anemic. His hemoglobin was 7 g dl–1 (normal 10–15 g dl–1) and platelet count was 20,000 per ml–1 (normal 150,000–250,000 ml–1). His white blood cell count was also lower than normal. The pediatrician sent John to a hematology consultant for a bone marrow biopsy. The biopsy showed that John’s bone marrow had very few cells and that red cell, platelet, and white cell precursors were almost completely absent. Aplastic anemia (bone marrow failure) of unknown cause was diagnosed. Aplastic anemia is ultimately fatal but can be cured by a successful bone marrow transplant. Fortunately, John had an HLA-identical 11-year-old brother who could be the bone marrow donor. John was admitted to the Children’s Hospital and given a course of busulfan to eradicate his own lymphocytes. He was then given 2 ¥ 108 nucleated bone marrow cells per kg body weight obtained from his brother’s iliac crests. John did well for 3 weeks after the bone marrow transplant and was then sent home to recover. However, on the 24th day after the transplant he was readmitted to hospital with a skin rash and watery diarrhea consistent with acute GVHD. On admission he had a patchy red rash on palms and soles, scalp, and neck. He had no fever and was not jaundiced. His lungs were clear and the heartbeat normal. The liver and spleen were not enlarged.

Graft-Versus-Host Disease

John was treated with corticosteroids and the immunosuppressive drug tacrolimus (FK506). His skin rash faded, but the intestinal symptoms did not abate and the diarrhea became more profuse. He was given a test dose of antithymocyte serum but developed a fever and shaking chills, so this therapy had to be discontinued. John developed diffuse bleeding from the colon and a colonoscopy revealed diffuse GVHD throughout the large bowel. After 6 weeks in which the watery diarrhea did not improve, John was given an anti-CD3 monoclonal antibody by intravenous injection, to try and eliminate the T cells, as well as octreotide (an inhibitor of intestinal vasoactive peptide) and another immunosuppresssive drug, mycophenolate mofetil. This therapy provided no relief of his symptoms, which were finally controlled by injection of a monoclonal antibody to CD2 (another cellsurface marker of T cells) every 3 days. This brought about a 90% decrease in the volume of his stool and the intestinal bleeding stopped. Treatment with anti-CD2 antibody was continued weekly for 2 months and his symptoms completely disappeared. John was sent home, with continuing treatment with low doses of corticosteroid, after 6 months of hospitalization for GVHD.

eloping; try GVHD devs. tacrolimu

ry sponding..T e r t o n t n Patie al antibodies monoclon

Graft-versus-host disease (GVHD). Graft-versus-host disease was first described over 30 years ago by Billingham, Brent, and Medawar, who gave allogeneic lymphocytes to newborn mice. The mice became runted (their growth was retarded), lymphoid tissue was destroyed, and they developed diarrhea and necrosis of the liver. GVHD was first recognized in human infants with severe combined immunodeficiency disease who inadvertently received allogeneic lymphocytes in a blood transfusion (Fig. 47.2). For a recipient to develop GVHD, the graft must contain immunocompetent cells, the recipient must express major or minor histocompatibility molecules that are lacking in the graft donor, and the recipient must be incapable of rejecting the graft.

Fig. 47.2 GVHD on trunk and limbs of affected infant.

The first clinical manifestation of GVHD is a bright red rash that characteristically involves the palms and soles. The rash usually begins on the face and neck and progresses to involve the trunk and limbs, particularly the palms and soles. The rash may itch a great deal and its onset may be accompanied by fever. After the skin manifestations appear (Fig. 47.3), the gastrointestinal tract becomes involved (Fig. 47.4) and profuse watery diarrhea is produced.

a

b

Fig. 47.3 GVHD in the skin. Panel a: early GVHD in the skin. Lymphocytes are emerging from blood vessels (lower arrow) and adhering to the basal layer of the epidermis (upper arrow). Panel b: the basal cells of the epidermis begin to swell and vacuolate. Their

c

nuclei become condensed (dark staining) as these cells die (arrow). Panel c: advanced destruction of the skin by GVHD, with sloughing of the epidermis (arrow). Photographs kindly provided by Dr Robert Sackstein.

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4

Graft-Versus-Host Disease

Liver function tests may become abnormal and reveal destruction of hepatic tissue (Fig. 47.5). Eventually, other tissues such as the lungs and bone marrow become sites of GVHD inflammation. The only satisfactory therapy at present for GVHD is elimination of the T cells that initiate the reaction, either by immunosuppressive drugs or, as in John’s case, by anti-T-cell monoclonal antibodies.

Fig. 47.4 GVHD in the colon. Inflammatory cells have invaded the crypts of the intestine and destroyed the normal architecture (arrow). Photograph kindly provided by Mark Shlomchik.

Some bone marrow transplant centers now routinely deplete donor bone marrow of T cells before transplantation, to try and avoid GVHD. But this treatment is still somewhat controversial and is not universally followed. Untreated bone marrow seems to provide a ‘graft-versus-leukemia’ reaction, which makes relapse less likely in the case of bone marrow transplants for the treatment of leukemia.

Questions. 1 Bone marrow is often depleted of T cells before transplantation in order to try and avoid GVHD. However, in the treatment of leukemia by bone marrow transplantation, T cells in the graft can have a beneficial effect. How do you explain this? 2 CD4 T cells in the graft that recognize foreign histocompatibility molecules become activated and produce the cytokine interferon (IFN)-g. This helps sustain and increase GVHD. Why? Fig. 47.5 Liver damage as a result of GVHD. Inflammatory cells have invaded the liver and destroyed the hepatic ducts (arrows). Photographs kindly provided by Dr Robert Sackstein.

3 John was given a monoclonal antibody to CD3 but it did not help him. When he was given an antibody to CD2, however, he showed sustained improvement. How do you explain this difference? 4

Why are the skin and intestinal tract the major sites of GVHD?

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Answer 1 The engrafted T cells appear to recognize allogeneic antigens on the recipient’s hematopoietic cells and thus will attack the leukemic cells. One such antigen, HB-1, which is a B-cell lineage marker, is expressed by acute lymphoblastic leukemia cells, which are B-lineage cells, and by B lymphocytes transformed by Epstein–Barr virus (EBV).

Answer 2 IFN-g induces the expression of MHC molecules on cells and this makes GVHD worse, as it provides more targets for the donor T cells.

Answer 3 It is not entirely clear why the anti-CD2 was more therapeutically efficacious compared with the anti-CD3. One reason might be that anti-CD3 antibodies rapidly cause the disappearance of CD3 molecules from the surface of T cells, and so the T cells can be no longer recognized by the antibodies, whereas anti-CD2 antibody does not have this effect on CD2.

Answer 4 One reason could be that the skin and intestine express a higher level of MHC molecules than other tissues. The intestinal tract is also likely to be damaged by the preparative cytotoxic treatments given to destroy the recipient’s bone marrow. The damage induces the production of cytokines: as well as inducing MHC molecules, these can also drive GVHD and make the tissue susceptible to immunological attack.

Answers