Organ transplantation has almost disappeared from headlines in the daily press, possibly because it failed to fulfill exaggerated expectations. Transplanta tion pathology has become more and more important, not only with relation to therapeutic transplantations but even more in its fundamental theories. There is some analogy here to the development in space science where spectacular achievements were followed by sobering frustrations and where, for the time being, the effect on technology is more fruitful than the outcome of the original far-reaching projects. That transplant rejection was defined, in most of its stages, as an immunologic process, has given many new impulses to immunology in general. Transplantation assays have become a pet experiment in immunobiology and an abundant source of general information and knowledge. The implications of such a development could not be predicted when the present volume was outlined and planned. In accordance with the concept of WILLI MASSHOFF, general transplantion pathology was given a central position as a fundamental science, while the chapters on the transplantation of various tissues are of a more paradigmatic character. It was MASSHOFF who invited competent authors and who managed to balance their articles, despite some overlapping, so as to draw a comprehensive picture of contemporary transplanta tion pathology. WILLI MASSHOFF died while he was editing the first manuscripts. As co-editors we have undertaken to complete the publication that we began together.

The Main Histocompatibility System in Man

A. Introduction
B. Historical Background
C. Methodology and Serological Considerations
I. Leukoagglutination
II. Lymphocyte Cytotoxicity
III. Platelet Complement Fixation
IV. Serum Sources
1. Polytransfused Patients
2. Pregnancy
3. Immunization of Human Volunteers
4. After Organ Transplantation
5. "Natural" Lymphocytotoxins
6. Immunization of Animals
D. Genetics of the HL-A System
E. Heterogeneity and Cross-Reactivity of HL-A Antigens
F. HL-A, Mixed Lymphocyte Culture (MLC), Cell-Mediated Lympholysis (CML), and Cellular Immunity
G. HL-A System and Clinical Transplantation
I. Skin Graft Survival
II. Kidney Transplantation
III. Variability in the Host Immune Response
IV. Donor Selection for Kidney Transplantation
V. Bone Marrow Transplantation
H. HL-A System and Human Diseases
I. HL-A and Hematologic Malignant Diseases
II. HL-A and Cancer (other than Lymphomas)
III. HL-A and Immunopathic Diseases
IV. HL-A and Infectious Diseases
V. HL-A and Rheumatoid Diseases
VI. HL-A System and Various other Diseases
I. HL-A System and Blood Transfusion
J. HL-A System and Disputed Paternity Cases
K. Conclusions
References
Gene Products of the Major Histocompatibility Complex: Biology and Chemistry
1. Introduction
2. The MHC in Man and Animals
2.1 Similarities
2.2 Differences
3. Biology of Human MHC Products
3.1 HL A Antigens
3.2 ß2-Microglobulin (ß2m)
3.3 Ir-Region in Man
3.4 Association of HL A with Disease
4. Additional Information from Animal Studies
4.1 Genetics of the H-2 Complex
4.2 I-Region Traits and Functions
4.3 Donor Specific Prolongation of Transplant Survival
5. Chemistry of Human and Mouse MHC Gene Products
5.1 Homology
5.2Membranes and Models
5.3 Methods
5.4 Biochemistry of HL A/H-2 Antigens
5.5 ß-Microglobulin
5.6 Immune Response Region Associated Antigens (Ia)
6. Concluding Remarks
References
Lymphocyte-Defined Components of the Major Histocompatibility Complex
A. Introduction. General Principles of MLC
B. Technical and Statistical Aspects of Human MLC
I. Macro- and Micro-Methods
II. Determination of Non-Stimulation
1. Controls
2. Statistical Analysis
3. Quantitation of MLC Results
C. Mouse MLC Techniques
D. Genetics of MLC in Humans
I. Basic Principles
II. Correlation of MLC Non-Stimulation in Siblings with Inheritance of the Same HL-A Haplotype
III. Exceptional Cases of Stimulation and Non-Stimulation
IV. Association of Stimulation with Four-Locus Region
V. Minor loci
VI. MLC and HL-A Typing in Unrelateds
E. Genetics of MLC in the Mouse
F. MLC Typing
I. Principle of Typing-Use of Homozygous Cells
II. Problems in Defining a "Typing" Response
G. Cell-Mediated Lympholysis (CML) Reaction
I. CML in the Human
II. CML in the Mouse
III. Relation of CML and MLC
H. Correlations of MLC with Grafting
I. Conclusion
Appendix I. Statistical Definitions
Appendix II. Definition of Genetic Terms
Addendum
References
Phylogenetic Aspects of Transplantation
A. Introduction
B. Transplantation Reactions in Invertebrates Other than Annelids and Echinoderms
1. Organelle Transplantation in Protozoans (Sarcodina, Ciliata)
2. Metazoans-Specificity of Reaggregation in Porifera
3. Incompatibility in Cnidaria (Hydrozoa, Anthozoa)
4. Platyhelminthes and Sipunculida
5. Equivocal Incompatibilities in Mollusca (Pelecypoda, Gastropoda, Cephalopoda)
6. Arthropoda
7. Genetic Control in Urochordata
8. Summary of QuasiImmunorecognition
C. Transplantation Reactions in Invertebrates that Reveal Primordial Cell-Mediated Immunity
I. Short-term Immunologic Memory
II. Cell and Tissue Responses that Indicate Self Recognition in Echinoderms
III. Transplantation in Asteroidea
IV. Short-term Memory
V. The Earthworm Model
1. First- and Second-Set Allograft Rejection in Lumbricus terrestris and Eisenia foetida
2. Rejection of First- and Second-Set Xenografts Exchanged between Lumbricus and Eisenia
3. Specificity and Anamnesis
4. The Cellular Response
5. The Role of Temperature in Earthworm Tissue Graft Rejection
6. Summary
D. Transplantation Immunity in Fishes
I. Introduction
II. The Hagfish
III. The Lamprey
IV. Cartilaginous Fishes
V. Bony Fishes (Holosteans; Teleosts)
E. Transplantation Immunity in Amphibians
I. Adult Apodans
1. Introduction
2. General Description of Autografts and Allografts
3. Histopathology
II. Adult Urodeles
1. The Latent Phase
2. The Rejection Phase
3. The Chronic Rejection Response to Xenografts
4. Role of the Thymus in Graft Rejection
5. Histologic Differences in Skin
6. Suppression of Transplantation Immunity
III. Anurans
1. Larvae
2. Bone Marrow Restoration of Transplantation Immunity in Adult Leopard Frogs
F. Transplantation Immunity in Reptiles
I. Introduction
II. The Chronic Response in Turtles
III. The Importance of Temperature in Turtles
IV. The Mexican Iguana
V. The Garter Snake
References
Ontogenetic Aspects
A. Introduction
B. Ontogeny of Lymphoid Structures
C. Ontogeny of Transplantation Immunity
D. Ontogeny of Thymus-Dependent Functions
E. Concluding Remarks
References
Humoral and Cell-Mediated Mechanisms of Allograft Rejection
A. Introduction
B. Assay Methodsof Cell-Mediated Cytotoxicity (CMC)
C. Cytotoxicity Mediated by Specifically Sensitized T-Cells
D. In Vivo Formation of Cytotoxic T Lymphocytes
E. In Vitro Formation of Cytotoxic T Lymphocytes
F. Mechanism of T-Cell Cytotoxicity
G. Specificity of Target Cell Destruction by Cytotoxic T Lymphocytes
H. Antibody-Dependent Cytotoxicity Mediated by Normal Lymphoid Cells
I. Cytotoxicity Mediated by Macrophages
K. Relevance of CMC to Allograft Rejection
L. The Role of Antibody in Allograft Rejection
References
Cell Systems Participating in Graft Rejections
A. Introduction
B. Lymphocytes
I. Development of the Immune System and Lymphocyte Subclasses
1. Early Ontogenesis of Lymphoid Organs and Cells
2. Postnatal Development of the Lymphocytic Systems
3. The Central Role of the Thymus
II. Peripheral Lymphocytes
1. Lymphocyte Subclasses
a) T Cells
b) B-cells
c) Null Cells
2. The Functions of Peripheral Lymphocytes
a) Helper and Suppressor Activity
b) Cell-Mediated Cytotoxicity
c) Mixed Lymphocyte Cultures
d) Graft-Versus-Host Reaction (GVHR)
C. Macrophages
D. Neutrophilic Granulocytes
E. Other Cells and Structures
References
General Tolerance Phenomena
A. Introduction
B. Tolerance Phenomena and Other Specific Inhibitions of Immune Reactions
I. Inhibition States Classified as Immunologic Tolerance
1. The Sulzberger-Chase Phenomenon
2. Immunologic Paralysis
3. Tolerance to Heterologous Serum Proteins
4. Tolerance to Other Antigens
II. Other Antigen-Induced States of Specific Inhibition of the Immune Response
1. Immunologic Enhancement
2. Immune Deviation
C. Mechanisms of Immunologic Tolerance
I. The Relation of Antibody-induced Suppression to Immunologic Tolerance
II. Cellular Processes in Immunologic Tolerance
III. Suppressor Cells
IV. Transplantation Tolerance
V. Mechanism of Unresponsiveness to Self Components
D. Conclusions
References
Transplantation of Cells: Experimental and Clinical Observations
A. Introduction
B. Historical Notes
C. Cell Types Used for Transplantation and Indications for the Respective Procedure
I. Experimental Transplantation
II. Human Transplantation
1. Indications for Transplantation of Blood and its Components
2. Indications for Transplantation of Bone Marrow
D. Techniques of Cell Transplantation
I. Details of Patient Selection
1. Selection of the Host
2. Selection of the Donor
II. Preevaluation and Pretreatment of Host and Donor
1. Pretreatment of the Donor
2. Pretreatment of the Recipient
III. Procurement of Bone Marrow Cells
IV. Cell Grafting
V. Cells other than Bone Marrow Cells used for Transplantation in Man
VI. Posttransplant Clinical Investigation of Bone Marrow Recipient
E. Demonstration and Localization of Engrafted Cells
F. Graft-Host Interactions
I. Microenvironmental Influences
II. Graft Rejection
III. Graft-Versus-Host Reaction (GVHR)
IV. Therapeutic Intervention of Postengraftment Disease
G. Conclusions
References
Skin Grafts in Animals and Man
A. Introduction
B. Operational Definition of Transplant Antigens
C. Morphologic Changes Occurring in Skin Allografts
I. Sequential Changes in Gross and Microscopic Appearance
II. Characterization and Quantitation of the Infiltrating Cells
III. Comparison of Morphologic Events in the Homograft Reaction and in other Hypersensitivity Reactions
D. The Immune Responses Induced by Skin Grafting
I. Afferent Phase-Antigen Recognition
II. Central Phase-Clonal Proliferation, Yielding both Memory andDifferentiated Effector Cells
III. Effector Phase-the Expression of Immunity
1. Specific Immune Cytotoxic Mechanisms
2. Recruitment of Nonsensitized Effector Cells by Lymphokines Secreted by Sensitized T-Cells
3. Local Activation of the Host's General Inflammatory Response
4. Correlation of Immunologic and Pathophysiologic Events with Clinical Skin Graft Rejection Syndromes
IV. Autoregulatory Phase
1. Complete or Partial Tolerance
a) Conditions Affecting Induction, Maintenance, and Reversal of Immunologic Tolerance
b) The Absence of Reactive Cells or the Presence of Nonreactive Cells
c) The Presence of Immunologically Active Lymphocytes Blocked by Serum Factors
d) Other Alternatives: Suppressive or Regulatory Events Mediated by Lymphocytes on Immune Reactions
2. Immunologic Enhancement
a) General Features of Graft Survival
b) Relationship Between Organ Vascularity and Immunologic Enhancement
References
Transplantation of Connective Tissue
A. Introduction
B. General Section
I. Anatomic Structure of Connective-Tissue Types as it Affects Suitability for Transplantation
II. Viability and Nonviability: Denaturation of the Graft as it Affects Primary Healing and Restructuring
III. Biological and Mechanical Merits of Auto-, Homo-, and Heterologous Transplants
IV. Changes with Age in Connective Tissue as they Affect Transplantation
V. Immune Reactions in the Transplantation of Living and Preserved Connective Tissue
VI. Preservation
VII. Healing
C. Specific Section
I. Tendon
II. Cutis
III. Fascia
IV. Dura
D. Future Prospects
References
Transplantation of the Cornea in Man and Animal
I. Introduction and Historical Background
II. Basic Principles of Keratoplasty
A. Terminology
B. Indications forKeratoplasty
C. Criteria for Donor Material and Storage
1. General
2. Donor-Cornea Evaluation (Laboratory and Clinical)
3. Storage
D. Surgical Techniques in Keratoplasty
E. Factors Determining Prognosis of Keratoplasty
1. Quality of the Donor-Cornea
2. State of the Recipient Cornea
3. Other Ocular Disease
4. Quality of Surgery
F. Healing of the Corneal Wound in Keratoplasty
G. Fate of Donor Cells in Keratoplasty
III. Unsuccessful Keratoplasty
A. Nonimmunologic Factors for Graft Failure
B. Immunologic Reasons for Graft Failure
IV. Experimental Keratoplasty and Heterografting
References
General Pathology of the Transplantation Reaction in Experimental and Clinical Organ Grafts
A. The Many Facets of the Transplantation Reaction
I. Introduction
II. Terminology
1. Donor-Recipient Relationship
2. Chronologies of Rejection
III. Elements of the Transplantation Reaction
1. Dichotomy of the Immune Response
2. T-Helper Cell Mechanisms
3. Effector Mechanisms of Cell-Mediated Cytotoxicity
a) Autonomy of T-Lymphocyte Cytotoxicity
b) Mediators of the Cellular Immune Reaction
c) Cell-Mediated Cytotoxicity Independent of Thymus
IV. Humoral Factors Involved in Graft Rejection
B. Effector Cells and the Target Cell Injury
I. Morphology of Infiltrating "Lymphoid Cells"
1. Small Lymphocytes
2. Medium-Sized Lymphocytes
3. Atypical Lymphocytes
4. Large Lymphocytes
5. Transformed Lymphocytes
6. Lymphoid Killer Cells
7. Monocytes
8. Macrophages
II. Morphology of the Cell-Mediated Target Cell Destruction in vitro
1. Membrane Contact
2. Morphology of Cell-Mediated Target Cell Lysis
3. Morphology of Antibody-Dependent Cell-Mediated Cytotoxicity
4. Other Mechanisms of Cell-Mediated Target CellDestruction
III. Features of Antibody-Mediated Injury
1. Morphology of the Complement-Dependent Immune Cytolysis
2. Relationship Between Immune Complexes and Clotting
3. Pathogenesis of Tissue Injury Mediated by Immune Complexes
C. Pathways of Host Sensitization
I. Cellular Mechanisms
1. Central Reactions
2. Recirculation of Immunocompetent Cells
II. Pathways of Sensitization to Solid Organ Grafts
1. Soluble Antigens
2. Macrophage-Processed Antigen
3. Peripheral Sensitization
4. Passenger Leukocytes
D. Hyperacute Rejection
I. Pathogenesis
II. Pathology of the Hyperacute Rejection
1. Kidney
a) Course of Events
b) Cellular Mechanisms and Mediators Involved in Hyperacute Rejection
2. Heart
3. Liver
4. Lungs
5. Pancreas
III. Nonimmunologically Caused Primary Graft Failure and Damage
1. Pretransplantation Anoxemic Lesion
2. Mechanical Traumatization
3. Morphology of the Pretransplantation Ischemic and Mechanical Damage
a) Kidney
b) Heart
c) Liver
d) Lung
e) Pancreas
E. Accelerated (Delayed Hyperacute) Rejection
F. Acute (Intermediate) Rejection
I. Pathogenesis
1. Cellular Infiltration and Vascular Lesions
2. Mechanisms of Acute Cell-Mediated Graft Rejection
II. Particular Patterns of Acute Rejection
1. Kidney
2. Heart
3. Liver
4. Lung
5. Pancreas
6. Small Bowel
G. Chronic or Late Rejection
I. Arterial Obliterative Lesion
II. Interstitial Fibrosis, Parenchymal Atrophy and Chronic Cellular Infiltration
III. Chronic Glomerulopathy
H. Future Prospects of Organ Transplantation
I. Current Experience in Organ Transplantation
II. Histocompatibility Typing
III. Organ Preservation and Storage
1. Simple Hypothermic Storage
2. Short-Term Preservation
3. Intermediate-Term Storage and Long-Term Preservation
IV. Artificial Organs
V. Modification of the Immune Response
1. Immunosuppression
2. Immunologic Enhancement
3. Immunosuppressive Antibodies
4. Immunologic Tolerance
5. Specific Immunologic Unresponsiveness
6. Attempts to Render the Graft Nonantigenic
VI. Xenotransplantation
VII. Abbreviations and Definitions
References
Bone Transplantation in Animals and in Man
A. Introduction and Historical Review
B. Anatomy and Physiology of Intact Bone
1. Structural Elements of Bone
1.1. Osteoblasts
1.2. Osteoclasts
1.3. Osteocytes
1.4. Collagen
1.5. Amorphous Intercellular Substance
1.6. Hydroxyapatite
2. Transformation of Bone Tissue
2.1. Physiologic Transformation
2.2. Adaptation of Bone to Mechanical Forces
2.3. Pathologic Bone Transformation
C. Bone Transplantation
1. Blood Supply to Transplanted Bone Tissue
2. Osteogenesis in Autografts
2.1. Osteogenesis in Transplanted Periosteum
2.2. Osteogenesis in Transplanted Compact Bone
2.3. Osteogenesis in Transplanted Cancellous Bone
2.4. Osteogenesis by Induction
3. Immunology of Homologous and Heterologous Bone Transplantation
3.1. Bone Homografts
3.2. Bone Heterografts
4. Transplantation of Pretreated Bone Ground Substance
5. Conclusions Drawn From the Results of Experimental Bone Transplantation
D. Clinical Aspects of Bone Transplantation
1. Cancellous Bone Autografts
2. Clinical Scale of Merit of Autografts
3. Graft Bed
3.1. Stable, Well-Vascularized Bed
3.2. Secondarily Stable Bed With Impaired Vascularization (Pseudarthroses and Fresh Fractures)
3.3. Continuity Defects of the Long Bones
3.4. Grafting into a Septic Milieu
E. Conclusion
References
Radiation-Induced Tolerance
A. Introduction and History.-B. Humoral Immunity
I. Primary and Secondary Immune Response
II. Time of Irradiation and Antigen Injection
III. Radiation Type and Amount
IV. Type of Antigen
C. Cellular Immunity
I. Bone Marrow Grafting
1. Irradiation Dose
a) Injury
?) Hematopoietic
ß) Gastrointestinal
?) Central Nervous System (CNS)
b) Conditioning of Recipients for Hematopoietic Grafting
?) The Midlethal Dose (MLD) Effect
ß) Rejection of the Marrow Graft and "Reversal"
?) Exposure Rate Effects
?) Conditioning by Irradiation Other Than Total Body (TBI)
?) Time of Marrow Infusion in Relation to Irradiation
2. Histocompatibility Differences Between the Host and Donor
3. The Presensitized Recipient
4. Successful Hematopoietic Engraftment
a) Evidence of Chimerism
b) GVHD
?) Pathology
ß) The Prevention and Treatment of GVHD
c) Immunologic Reconstitution of Chimeras
d) Long-Term Survivors as Examples of Irradiation Induced Immunologic Unresponsiveness: "True Tolerance" or "Enhancement Phenomenon"?
e) Clinical Marrow Grafting Studies
?) Marrow Grafting in Hematologic Malignancy
ß) Marrow Grafting in Aplastic Anemia
?) Conclusions and Summary of Outstanding Problems in the Field of Irradiation and Clinical Marrow Grafting
II. Other Organ Grafts
References
Immunosuppression by Antibodies
A. Introduction
B. Concepts of Immunosuppression by Antibodies
C. Xenogeneic Antilymphocyte Sera
I. General Aspects
II. Types of Xenogeneic Antilymphocyte Sera
III. Effects on Lymphoid Cells in vitro
IV. Effects on the Lymphatic System
V. Immunosuppressive Activity of ALS
1. Humoral Immunity
2. Delayed Hypersensitivity
3. Transplantation Immunity
4. Autoimmune Phenomena
5. Graft-Versus-Host Immunity
VI.Cooperative Effects With Other Immunosuppressive Regimens
VII. Assays for Immunosuppressive Potency
VIII. Mode of Action
IX. Side-Effects and Complications
1. Toxic Effects
2. Hyperergic Reactions
3. Infections
4. Neoplasms
X. Immunosuppression with ALS in Humans
D. Passive Enhancement
I. General Aspects
II. Types of Antibodies Initiating Enhancement
III. Prolongation of Allograft Survival by Passive Enhancement
IV. Immune Status of Passively Immunized Allograft Recipients
V. Mechanisms of Enhancement
VI. Side-Effects and Complications
VII. Immunologic Enhancement in Humans
References
Medications and Their Toxicity
A. Introduction
B. Pharmacology and Immunopathology
I. Adrenocorticosteroids
II. Alkylating Agents
III. Antimetabolites
IV. Vinca Alkaloids
V. L-Asparaginase
VI. Miscellaneous Agents
VII. Antilymphocyte Sera (ALS)
C. Toxicology and Adverse Effects
I. Adrenocorticosteroids
II. Alkylating Agents
III. Antimetabolites
IV. Vinca Alkaloids
V. L-Asparaginase
VI. Miscellaneous Agents
VII. Antilymphocyte Sera (ALS)
D. Special Topics
I. Infection
II. Carcinogenesis
E. Summary
References
Graft-Versus-Host-Reactions
1. Introduction
2. Experimental Models
2.1. Systemic GVHR
2.1.1. Juvenile Forms
2.1.1.1. Chorioallantoic Membrane Test
2.1.1.2. A ? A + B Type
2.1.1.3. DA ? Fischer + DA-Type
2.1.2. Adult Forms
2.1.3. Reaction Parameter
2.1.3.1. Weight of the Spleen
2.1.3.2. Number of Lymphocytes
2.1.3.3. Body Weight
2.1.3.4. Survival Time
2.1.3.5. Phagocytosis Index
2.1.3.6. Other Reaction Parameters
2.2. Local GVHR
2.2.1. The Intrarenal Form
2.2.2. The Intracutaneous Form
2.2.3. Popliteal Lymph Node Test
2.2.4. The Intra-Ocular Form
2.3. In-VitroAnalogies
2.3.1. The Mixed Lymphocyte Culture
2.3.2. The Spleen Expiant Test
3. Clinical Observations
3.1. "Spontaneous" GVHD in Humans
3.2. GVHD After Bone Marrow Transplantation
3.2.1. In Case of Primary Immuninsufficiency or Aplastic Anemia
3.2.2. In Leukemias
3.2.3. After Blood Transfusions
4. Histopathology
4.1. Mice
4.1.1. Spleen
4.1.2. Lymph Nodes
4.1.3. Liver
4.1.4. Skin
4.1.5. Bone Marrow
4.1.6. Other Tissues
4.2. Rats
4.2.1. Spleen
4.2.2. Lymph Nodes
4.2.3. Liver
4.2.4. Skin
4.2.5. Bone Marrow
4.2.6. Other Tissue
4.3. Chickens
4.4. Other Animals
4.5. Humans
4.5.1. Spleen
4.5.2. Lymph Nodes
4.5.3. Liver
4.5.4. Skin
4.5.5. Gastrointestinal Tract
4.5.6. Bone Marrow
4.5.7. Remaining Tissue
5. Hematology
5.1. Mice
5.2. Rats
5.3. Other Species of Animals
5.4. Humans
6. Causal Pathogenesis
6.1. Immunologic Factors
6.2. Unspecific Factors
7. Formal Pathogenesis
7.1. Trigger Antigens
7.2. Immunocompetent Lymphocytes
7.3. Behaviour of Donor Lymphocytes
7.3.1. Nidation
7.3.2. Proliferation
7.3.3. Cellular Interactions
7.4. Behaviour of Host Cells
7.4.1. Damages
7.4.2. Reactive Hyperplasia and Allogenetic Effect
7.4.3. Immune Suppression
7.5. Mechanisms of Immune Regulations
8. Therapeutic Influence
8.1. Results of Experiments with Animals
8.1.1. Treatment of Donor Animals
8.1.2. Treatment of Donor Cells
8.1.3. Treatment of Host Animals
8.2. Clinical Results
9. Late Complications
9.1. Glomerulonephritis
9.2. Other Forms of Allogeneic Diseases
9.3 Malignant Tumors
10. Prospects
References
Author Index.