It is currently accepted that intolerance to homografts belongs in the general category of actively acquired immunity. Purportedly, when tissues are homotransplanted the nuceli of grafted cells give off compounds similar to the blood group mucoids. It is possible that these antigens are aminoacid polysaccharide complexes. This material enters the lymphatics, travels to the regional lymph nodes, and there initiates the production of cellular antibodies. These in turn reach the graft via the blood stream and bring about rejection of the homograft. Although the intra-cellular antibody-like substances are the only ones with a firmly established role in the rejection of transplants there is increasing evidence that serum antibodies may also play a part in the mechanism of rejection. Investigations have shown that a homograft might be capable of reacting against its host. This reaction of graft versus host must be borne in mind when one considers the possibility of introducing immunologically active cells into human beings. Use of embryonic tissue or prior radiation of the graft has been shown to obviate the response of graft versus host. When skin grafts are rejected, the vascular changes consist of a sudden reduction in the caliber of the larger graft vessels with a slowing down of the rate of flow; however, unless sepsis is present, thrombosis in the vessels of the graft bed does not occur. A transplant will grow only when the host carries certain dominant genes which were present in the animal from which the tissue originated. Nature provides at least five exceptions to the concept that skin grafts between individuals are invariably destroyed, (1) Identical twins accept grafts. Inbred animal strains develop such a high degree of genetic uniformity so as to behave as identical twins. (2) Embryos or sometimes neonatal individuals accept grafts. (3) Patients with agammaglobulinemia tolerate homologous skin. (4) Chimeras will not reject grafts. This phenomenon of natural tolerance occurs in cattle twins and has been reported in non-identical human twins. The possibility of tolerance to grafts between a mother and child has been reported. (5) Skin taken from embryos (first trimester of pregnancy) is frequently accepted when grafted to adults. The first and third exceptions have been proved in man. Knowledge of these natural exceptions to the rejection of grafts exchanged between two individuals may, on occasion, be life saving. On the basis of an extremely close genetic relationship or chimerism, non-identical twins may tolerate grafts exchanged between them. Grafts between a mother and her offspring may not be rejected. Other natural exceptions may also exist. It should not be assumed that all reports of successful grafting are erroneous. We believe that possibly in some cases it is a mistake to credit the success of an interchangeable graft to a specifically utilized therapy rather than to a natural exception. In general there are three approaches being studied to prolong the life of homografts: (1) altering the antigenic propensity of the graft; (2) transplanting the graft to a privileged site, either the natural anterior chamber of the eye or a millipore chamber with pores too small to allow the passage of cellular antibodies; and (3) eliminating or lessening host resistance. Probably the third approach offers the greatest promise. Among the procedures and conditions which have been reported to prolong graft survival by acting through the host are included pregnancy, administration of local or systemic adrenal hormones, splenectomy, nitrogen mustard therapy, anticoagulant therapy, desensitization, reduction in serum properdin titers, production of immunologic tolerance, chronic uremia, total radiation of the body, reduction of the antitryptic titer, use of antihistaminic drugs, hypophysectomy and/or thyroidectomy, plasmapheresis, production of pyridoxine deficiency, and extensive burns. The phenomenon of tissue therapy is discussed. It has been postulated that when tissue which is removed exists in an unfavorable environment, such as a refrigerator, it produces substances called biogenic stimulators. These supposedly catalyze normal body reparative processes when the tissue is transplanted. A considerable body of evidence has now accumulated which shows that tumor grafts will survive a degree of immunological opposition sufficient to bring about the demise of a homologous skin graft. The present status of the following transplantable tissues is discussed:. Blood Vessels. Arterial homografts, arterial heterografts, autogenous vein grafts, plastic materials, autoplastic cutis, autogenous skin and autogenous bowel have been used for vessel replacement. None of these is an ideal vascular prosthesis. The common denominator determining the histologic fate of aortic and femoral homografts is according to Szilagyi "the intrinsic structural makeup that characterizes elastic and muscular arteries respectively." The connective tissue replacement of arterial homografts is enhanced by a rich complement of biologically inert elastic fibers in the vessel wall and hindered by a high relative proportion of biologically active smooth muscle cells. The longer the follow-up the greater is the degeneration which occurs in aortoiliac and femoral homografts. Plastics for vascular replacement are being intensively studied but the follow-up period is shorter than has been carried out with homografts so comparisons are difficult to make. Autogenous vein grafts make satisfactory replacements for peripheral vessels. Although arterial homografts do degenerate over a several-year period and the trend is towards plastics, the latter have not been shown to be functionally superior to homologous artery for the replacement of peripheral vessels. At this writing there is no long range, satisfactory arterial substitute. Bone. Great confusion still exists concerning the fundamental principles underlying transplantation of bone. Osteocytes in autogenous bone grafts survive as living entities. Osteocytes in homologous bone grafts, transplanted in contact with host bone, die after transfer. In preserved grafts they are presumably dead at the time of transplantation. Both fresh and preserved homologous grafts are replaced in kind by new living bone cells from the host. Human autologous bone grafts such as rib, tibia and ileum must be transplanted in juxtaposition to bone in order to survive. Human membranous bones retain their calcified structure when transferred to areas of soft tissue. Complete human autologous phalanges with tendons, joints and nails will retain their structure after burial in abdominal fat for periods of at least nineteen months. Although grafts with periosteum obtain an earlier blood supply than those without periosteum, the present consensus is that periosteum is not essential for successful autologous transplantation of bone in contact with bone. Anorganic bone grafts prepared by ethylenediamine extraction of beef bone and sterilized by autoclaving have been used effectively to fill bone defects in patients. Despite the fact that homologous and possibly anorganic heterologous bone grafts have a place in surgery, autologous bone grafts when available are to be preferred. Healing is certainly more rapid with autologous grafts. Bone Marrow. Transplantation of homologous and heterologous bone marrow can be accomplished in radiated rodents. Less success occurs in the dog and monkey. If functional grafts of homologous bone marrow are to be obtained in a high percentage of animals, the recipients must have received supralethal doses of radiation. Use of embryonal blood-forming tissue is promising. Transplantation of autologous bone marrow administered intravenously is being clinically evaluated. Long term, complication free, transplantation of homologous marrow in human beings has yet to be realized. Cartilage. Both autologous and homologous cartilage will survive transplantation. Possible explanations for the survival of cartilage homografts include the avascular nature of the graft and the fact that the mucopolysaccharide matrix acts as a barrier against host cellular antibodies. Cornea. Corneal tissue which is known to be dead cannot be transplanted with the expectation of more than an occasional success. Cells in a fresh corneal homograft are apparently replaced by host stromal cells. Cornea which is transplanted subcutaneously is destroyed as promptly as a skin homogratt in the same location. The absence of blood vessels in the anterior chamber appears to permit corneal homotransplants to survive with the percentage of success varying inversely with corneal vascularity. Dura. Replacing the dura prevents the formation of dense meningocerebral adhesions and spinal fluid leaks. Autologous fascia lata is satisfactory. Homologous dura may be the best currently available material. Endocrine Tissues. An impressive group of studies indicates that homotransplants of at least some endocrine tissues do not provoke the usual rejection reaction. One of the theories frequently advanced to explain the wide variation in end results when endocrine tissue is autologously or homologously transplanted is Halsted's Law, which states that a deficiency must be created before transplanted endocrine tissue will take and survive. The weight of recent experimental evidence tends to disprove Halsted's thesis. All reported clinical success in homologously transplanted endocrine tissue, whether it be from a stillborn infant, following adaptation in the recipient's serum, or in millipore chambers, must be measured against the fact that endocrine tissue frequently behaves differently from skin when transplanted, possibly because it has fewer "histocompatibility genes" than skin. Fascia. Autologous fascial cells remain viable after transfer. Both homologous and heterologous fascia are replaced by host tissues although they retain their fascial structure. Fat. Recent evidence has been advanced to show that fat cells will survive autologous transplantation. Fresh homologous grafts of fat are completely replaced by host fibrous tissue. Autogenous grafts of fat with the dermis attached appear indicated for reconstruction of the breasts, hemiatrophy of the face and lipodystrophy. Mucous Membrane. Urethral reconstruction has been accomplished with free autografts of vesical mucosa. When the transitional-celled surface faced the lumen, formation of bone did not occur. In general it can be said that the behavior of homologous and autologous grafts of mucous membrane is similar to skin with the obvious exception that formation of bone does not occur in the latter. Nerve. The use of millipore chambers to bridge peripheral nerve defects and thus permit an orderly regeneration of neural elements appears promising. Organs. The kidney, liver, lung, heart, spleen, pancreas, female breast and entire head have been transplanted in experimental animals. Among the organs, the kidney has received the most attention. In general, autologous transplants of kidney placed into the pelvis of dogs will function indefinitely. Homologous transplants regardless of location function an average of about four days. The kidney has been utilized to demonstrate that grafted tissue reacts against its host before it in turn succumbs to the reaction of the host. In human beings permanent survival of transplanted kidney is possible between identical twins. Homologous transplants of kidney occasionally survive for long periods in uremic patients. Large scale clinical usefulness of homologously transplanted organs awaits the solution of the mechanism of homograft rejection. Teeth. Dental reimplantation describes the procedure of reinserting into the alveolar socket a tooth which has been accidentally extracted or dislodged due to trauma. Over 50 per cent of reimplanted teeth maintain their viability. Autogenous transplantation of teeth is most commonly employed for replacement of the first molar, held to be the key to the dental arch, by the third molar. Success attends the procedure in a high percentage of cases. Homologous transplantation of teeth is usually of no value. Preservation of Tissues. There are three general methods for tissue preservation: (1) preservation of viability in a nutrient medium at temperatures above freezing; (2) preservation in a non-viable state by freeze-drying or chemical fixation; and (3) preservation by freezing in either a viable or non-viable state. Almost all tissues which are transplantable in a fresh state have been transplanted after short periods of preservation in a nutrient medium. However, the relatively rapid deterioration of grafts preserved by tissue culture in addition to the strenuous efforts needed for satisfactory maintenance lessen the value of the method. Homostatic tissues such as blood vessels or bone in which viability is not necessary for satisfactory transplantation can be preserved by freeze-drying. Since freeze-dried homostatic tissues can be stored at room temperature, the technique is to be preferred to preservation of blood vessels and bone by freezing alone. Freezing represents a potentially practical long term method for preservation of tissues in the living state. Saturation with glycerol will protect isolated cells and tissues against the lethal effects of slow freezing. In slow freezing only extracellular ice crystals form; in rapid freezing the cooling rate is sufficiently high to cause intracellular growth of crystals. Spermatozoa, blood, skin, hone marrow, dura, cornea, platelets and ovaries, following presaturation with glycerol can be stored in a viable state by freezing. No review fulfills its function unless the reader finishes with some idea of not only what has been done but what avenues of future research appear to be promising. Homologous transplantation of many tissues is being attempted when, in fact, optimal techniques for the successful autologous transfer of the particular material have not been elucidated. It is our opinion that further investigations in the fields of tolerance, the chemical nature of cellular antigens, and the stromal reaction to transplantation should prove most fruitful. Although the barrier to successful clinical homotransplantation remains high, it is not insurmountable.
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