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A History of Bone Marrow Transplantation

  • M. Teresa de la Morena
    Correspondence
    Corresponding author.
    Affiliations
    Department of Pediatrics and Internal Medicine, Division of Allergy and Immunology, University of Texas Southwestern Medical Center in Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063, USA
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  • Richard A. Gatti
    Affiliations
    Department of Pathology and Laboratory Medicine, 675 Charles Young Drive South, Room 4-736, Macdonald Research Laboratories, University of California Los Angeles School of Medicine, Los Angeles, CA 90095-1732, USA
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      Keywords

      Five decades ago, the concept of bone marrow transplantation to treat humans with inherited diseases of immune function, marrow failure syndromes, and leukemia was met with much skepticism, degrees of enthusiasm, and many disappointments. Transferring what was known from experimental animal models to humans was met with many challenges, and such beginnings were very difficult. Certain death due to the primary disease, characterized the outcomes of individuals who were considered for transplantation. Consequently these patients became the sickest on the medical wards, and the physicians caring for such patients were posed with many questions regarding the benefits of such attempts. One of the major obstacles, graft-versus-host disease (GVHD) was “incomparably more violent than in (inbred) rodents” as stated by Bekkum and van de Vries.
      • Bekkum D.W.
      • van de Vries M.J.
      Radiation chimaeras.
      Yet through the recognition and subsequent understanding of fundamental immunologic processes, medical resiliency, and the stubborn determination of a few pioneers, bone marrow transplantation changed from an insurmountable therapeutic option for a limited number of patients to a form of therapy for 30,000 to 50,000 people worldwide annually.
      The Medical College of Wisconsin and The National Marrow Donor Program. Center for International Blood and Marrow Transplant Research (CIBMTR).
      Hematopoietic stem cell transplantation (HSCT) today is no longer a treatment modality for lethal diseases such as primary immunodeficiency diseases (PIDs) or malignancies but a valid approach of “cellular engineering”
      • Good R.A.
      • Kapoor N.
      • Reisner Y.
      Bone marrow transplantation—an expanding approach to treatment of many diseases.
      for solid tumors, hemoglobinopathies, autoimmune diseases, inherited disorders of metabolism, histiocytic disorders, and other nonmalignancies.
      The Medical College of Wisconsin and The National Marrow Donor Program. Center for International Blood and Marrow Transplant Research (CIBMTR).
      This article represents a historical perspective of the early investigators and their contributions. It also reviews the parallel work that oncologists and immunologists have undertaken to treat both PIDs and hematologic malignancies.

      The early days

      The idea of removing damaged parts of the body and replacing them with healthy organs has been an aim shared by physicians since ancient times. An early discussion on the use of bone marrow was outline in 1896 by Quine in the Chairman's address of the Journal of the American Medical Association, where he discussed the “remedial application of bone marrow extracts.”
      • Quine W.M.E.
      The remedial application of bone marrow.
      However, the physical consequences of World War II brought research in tissue transplantation to the forefront: skin grafts were needed for burn victims; blood transfusions required careful ABO blood typing and monitoring of blood group antibodies; and high doses of radiation lead to marrow failure and death, with little understanding of radiobiological mechanisms.
      By the early 1940s, it was clear that phagocytes were macrophages, antibodies were part of the gamma-globulin fraction of serum proteins (as defined by their electrophoretic mobility),
      • Tiselius A.
      • Kabat E.A.
      An electrophoretic study of immune sera and purified antibody preparations.
      and the “small lymphocytes” were influenced by adrenal hormones.
      • White T.F.
      • Dougherty A.
      Functional alterations in lymphoid tissue induced by adrenal cortical secretion.
      At the request of the Medical Research Council during World War II, Medawar
      • Medawar P.B.
      The experimental study of skin grafts.
      started work on the study of rejection of skin grafts, a priority for the treatment of burn victims. Early versions of immunologic tolerance and alloreactivity were published. In 1945, Ray Owen in Wisconsin, while studying the inheritance of blood group antigens in freemartin cattle, described how fraternal twin cattle were chimeric for 2 blood groups, their own and that of the twin.
      • Owen R.
      Immunogenetic consequences of vascular anastomoses between bovine twins.
      At the turn of the century, Loeb
      • Loeb L.
      Heredity and internal secretion in the spontaneous development of cancer in mice.
      had been unable to transfer tumors from Japanese waltzing mice to different strains of mice, whereas such tumors grew easily within the inbred strain. To Gorer
      • Gorer P.A.
      The detection of antigenic differences in mouse erythrocytes by employment of immune sera.
      and subsequently to Snell,
      • Snell G.D.
      • Stevens L.C.
      Histocompatibility genes of mice. III. H-1 and H-4, two histocompatibility loci in the first linkage group.
      • Snell G.D.
      Histocompatibility genes of the mouse. I. Demonstration of weak histocompatibility differences by immunization and controlled tumor dosage.
      • Snell G.D.
      • Jackson R.B.
      Histocompatibility genes of the mouse. II. Production and analysis of isogenic resistant lines.
      we owe the identification of the major histocompatibility complex (MHC) genes in rodents (H-2 system in the mouse).
      Medawar assimilated this background and provided convincing evidence that graft rejection was an immunologic phenomenon
      • Medawar P.B.
      The experimental study of skin grafts.
      linked to histocompatibility antigens. Subsequently with Billingham and Brent, he designed a series of hallmark experiments, in which he demonstrated the induction of immunologic tolerance.
      • Billingham R.E.
      • Brent L.
      • Medawar P.B.
      Actively acquired tolerance of foreign cells.
      Yet within the first few lines of the article, he cautioned that the experiments described were “…only a ‘laboratory’ solution of the problem of how to make tissue homografts immunologically acceptable to hosts which would normally react against them.”
      Massive radiation exposures provided an opportunity to advance therapies for bone marrow failure syndromes and leukemia. A series of critical studies in mice, dogs, and subsequently nonhuman primates that were subjected to high doses of radiation followed by transplantation of marrow grafts provided the basis for understanding concepts of histocompatibility, conditioning, graft-versus-leukemia effect, and GVHD.
      Jacobson and colleagues
      • Jacobson L.O.
      • Simmons E.L.
      • Marks E.K.
      • et al.
      Recovery from radiation injury.
      reported that the shielding of spleen, part of the liver, the head, or even 1 hind leg of mice allowed survival after total body irradiation. They also demonstrated similar protection if spleen grafts were transplanted intraperitoneally immediately after radiation exposure. These investigators posited that this phenomenon could be due to “a substance of a non-cellular nature” or that irradiation produced a “toxin” which was “detoxified” by shielding the spleen or the grafting tissues.
      • Jacobson L.O.
      • Simmons E.L.
      • Marks E.K.
      • et al.
      Recovery from radiation injury.
      By 1954, this “humoral” hypothesis was clearly trumped by the “cellular” hypothesis. Barnes and Louitit
      • Barnes D.W.
      • Ford C.E.
      • Ilbery P.L.
      • et al.
      Tissue transplantation in the radiation chimera.
      suggested that living cells were responsible for hematopoietic recovery after radiation. Shortly thereafter, many independent investigators confirmed that after lethal radiation, hematopoietic recovery was dependent upon donor cells.
      • Main J.M.
      • Prehn R.T.
      Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow.
      • Ford C.E.
      • Hamerton J.L.
      • Barnes D.W.
      • et al.
      Cytological identification of radiation-chimaeras.
      • Crouch B.G.
      • Overman R.R.
      Chemical protection against x-radiation death in primates: a preliminary report.
      Experienced with marrow transplant work in rodents, Mathé and colleagues
      • Mathé G.
      • Jammet H.
      • Pendie N.
      • et al.
      Transfusions et greffes de moelle osseuse homologue chez des humaine irradies a haute dose accidentellement.
      in France was faced with the need to rescue 5 subjects who had accidentally been exposed to high doses of radiation. He used bone marrow infusions from different donors. Of the 5 subjects, 4 survived. Subsequently it was recognized that this was because of autologous recovery. His group went on to describe early trials of adaptive immunotherapy with marrow grafts for the management of leukemia patients. Even though all patients died, complete remission from the leukemia was described for several patients for periods of 5 and 9 months before they died of either infection or the secondary disease (today known as GVHD).
      • Mathe G.
      • Amiel J.L.
      • Schwarzenberg L.
      • et al.
      Adoptive immunotherapy of acute leukemia: experimental and clinical results.
      At around the same time, Thomas and colleagues
      • Thomas E.D.
      • Lochte Jr., H.L.
      • Lu W.C.
      • et al.
      Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy.
      in the United States attempted human bone marrow transplants for leukemia. Five subjects with end-stage malignancies were infused with marrow from fetuses and adults. These investigators made special efforts to demonstrate that all collections were free of infection and were infused safely in the subjects without immediate transfusion reactions. Unfortunately none of the patients survived. Parenthetically, they also opined that although bone marrow is a source of plasma cells, patients with agammaglobulinemia, which had been recently described by Bruton,
      • Bruton O.C.
      Agammaglobulinemia.
      • Bruton O.C.
      • Apt L.
      • Gitlin D.
      • et al.
      Absence of serum gamma globulins.
      need not be treated with this modality because these patients did well on infusions of gamma globulin and antibiotics.
      • Thomas E.D.
      • Lochte Jr., H.L.
      • Lu W.C.
      • et al.
      Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy.
      This remains true today, 50 years later, with the one caveat that some of these patients develop progressive and fatal encephalitis
      • Medici M.A.
      • Kagan R.M.
      • Menkes J.
      • et al.
      Chronic progressive panencephalitis in hypogammaglobulinemia: a literature review.
      that might be averted by bone marrow transplantation.
      As had been previously reported, marrow grafting experiments in dogs were subject to the same consequences as noted in mice: after radiation, the animals could recover promptly if rescued with autologous marrow.
      • Mannick J.A.
      • Lochte Jr., H.L.
      • Ashley C.A.
      • et al.
      Autografts of bone marrow in dogs after lethal total-body radiation.
      In contrast, when allogeneic grafts were used, the graft was rejected, indicative of the immune competence of the animal, or successful engraftment was achieved, followed by lethal GVHD. Most importantly, it was already becoming clear that successful allogeneic marrow transplants, unlike solid organ transplants, depended upon close histocompatibility matching between donor and recipient and, thus, would be limited by the availability of donors. GVHD (the former) and histocompatibility (the latter) represented two hurdles that needed to be surmounted before bone marrow transplantation could be generally applied as a therapeutic modality for many.

      The challenges of GVHD

      At the same time that these early transplants were being performed for treatment of leukemia, the classification of PIDs was being refined. Attempts to correct lymphopenia with conventional blood transfusions were unsuccessful and often fatal.
      • Miller M.E.
      Thymic dysplasia (“Swiss agammaglobulinemia”). I. Graft versus host reaction following bone-marrow transfusion.
      In 1967, the first symposium on the immunologic deficiencies in man took place in Sanibel Island, Florida.
      Severe combined immunodeficiency (SCID), until then divided into Swiss type agammaglobulinemia (ie, autosomal recessive) or sex-linked lymphopenic immunologic deficiency, was attributed to thymic dysfunction. However, unlike the situation in DiGeorge syndrome, thymus transplants in SCID were not corrective. DeVries and colleagues
      • de Vries M.J.
      • Dooren L.J.
      • Cleton F.J.
      Graft versus host or autoimmune lesions in the Swiss type of agammaglobulinemia.
      suggested that the thymus defect might be secondary and hypothesized that the absence of lymphoid progenitors was the root cause of the combined defect. It made sense then to reconstitute such SCID infants with a source of lymphoid precursors, such as spleen, fetal liver, and bone marrow. Thus, in contrast to patients with leukemia, the main barrier was not rejection of the graft or relapse of leukemia, it was the terrible secondary disease or GVHD (Fig. 1).
      Figure thumbnail gr1
      Fig. 1GVHD in a patient who developed fever, maculopapular rash, hepatosplenomegaly, pancytopenia, and death.
      In August of 1968, an editorial was published by Hong and colleagues,
      • Hong R.
      • Cooper M.D.
      • Allan M.J.
      • et al.
      Immunological restitution in lymphopenic immunological deficiency syndrome.
      outlining the hazards and potential benefits of blood transfusions in immunologic deficiencies. It was proposed that either “old blood” or irradiated blood products be used in severely immunodeficient patients as a means of preventing GVHD. These authors further hypothesized that if one could find a histocompatible match, the immunologic capacity of the immunodeficient host could potentially be restored.
      The first HLA antigens in man were described by Dausset
      • Dausset J.
      in France, van Rood and colleagues
      • van Rood J.J.
      • van Leeuwen A.
      • van Santen M.C.
      Anti HL-A2 inhibitor in normal human serum.
      in Holland, Payne and Rolfs
      • Payne R.
      • Rolfs M.R.
      Fetomaternal leukocyte incompatibility.
      and Amos
      • Amos D.B.
      Genetic and antigenetic aspects of human histocompatibility systems.
      • Amos D.B.
      • Seigler H.F.
      • Southworth J.G.
      • et al.
      Skin graft rejection between subjects genotyped for HL-A.
      in the United States, and Ceppellini and van Rood
      • Ceppellini R.
      • van Rood J.J.
      The HL-A system. I. Genetics and molecular biology.
      in Italy. Terasaki and McClellan
      • Terasaki P.I.
      • McClelland J.D.
      Microdroplet assay of human serum cytotoxins.
      had developed methodology for a rapidly expanding panel of HLA antigens. A second HLA-Class I locus (HLA-B) had not yet been fully appreciated, most likely because of the high degree of linkage disequilibrium between the closely linked HLA-A and B loci (ie, 1 cM). Continuing studies in mice and dogs consistently demonstrated that if animals were well matched, GVHD could be prevented.
      • Simonsen M.
      Graft versus host reactions. Their natural history, and applicability as tools of research.
      • Good R.A.
      • Martinez C.
      • Gabrielsen A.E.
      Progress toward transplantation of tissues in man.
      • Storb R.
      • Epstein R.B.
      • Bryant J.
      • et al.
      Marrow grafts by combined marrow and leukocyte infusions in unrelated dogs selected by histocompatibility typing.
      Occasionally mild reactions occurred, but these were thought to be transient.
      With this background of imperfect but rapidly developing knowledge, including the experience being accrued by oncologists,
      • Thomas E.D.
      • Lochte Jr., H.L.
      • Lu W.C.
      • et al.
      Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy.
      • Thomas E.D.
      • Epstein R.B.
      • Eschbach Jr., J.W.
      • et al.
      Treatment of leukemia by extracorporeal irradiation.
      a window in history opened when the “right” patient was referred to Robert A. Good, then at the University of Minnesota (discussed in the next section).

      Renewed hope for SCID patients

      In the late 1950s, X-linked SCID was described (today known as common gamma chain–deficient SCID or γc-SCID). Most likely, this combined immunodeficiency is severe because the defective γ-chain is common to 5 interleukin (IL) receptors (IL-2, IL-7, IL-9, IL-15, and IL-21). Children with this disorder would come to medical attention early in life and die shortly thereafter with recurring and finally overwhelming infections, such as persistent thrush, fatal pneumonias, vaccinia gangrenosa, and susceptibility to Pneumocystis. In Sweden at that time, bacille Calmette-Guérin (BCG) vaccination for tuberculosis was mandatory, and about a dozen deaths were recognized related to this immunologic deficiency.
      • Good R.A.
      • Fisher D.W.
      A 5-month-old male child was referred to the University of Minnesota. The baby had previously been diagnosed in Boston as having “thymic alymphoplasia and agammaglobulinemia” (or X-linked SCID). The family history was significant for 11 male deaths over 3 generations. All had died of infections in early infancy (Fig. 2).
      • Good R.A.
      Immunologic reconstitution: the achievement and it's meaning.
      The patient had low serum gamma globulins and was being treated with gamma globulin injections and antibiotics for persistent pneumonia. A chest radiograph revealed absence of thymus. Hematologic studies noted lymphopenia. Antibodies against blood group antigens, diphtheria toxoid, and typhoid antigens were not detected. Cellular responses were absent. Tonsils, adenoids, and peripheral lymph nodes could not be detected.
      • Gatti R.A.
      • Meuwissen H.J.
      • Allen H.D.
      • et al.
      Immunological reconstitution of sex-linked lymphopenic immunological deficiency.
      Figure thumbnail gr2
      Fig. 2Patient family pedigree.
      (Adapted from Good RA. Immunologic reconstitution: the achievement and it's meaning. In: Bergsma D, Good RA, editors. Birth defects original articles series, vol. 4. White Plains (NY): The National Foundation-March of Dimes; 1968; with permission.)
      The most hopeful piece of information was that the child had 4 sisters, for this increased the chances of finding a matched sibling for marrow transplantation. Two forms of histocompatibility testing were developing at the time: (1) serologic typing for HLA (Class I only) and (2) cellular typing by mixed leukocyte cultures (MLCs).
      HLA typing was performed by Terasaki at the University of California, Los Angeles. Of all sisters analyzed, 1 was found to be the best match. MLCs, performed by Meuwissen
      • Meuwissen H.J.
      • Gatti R.A.
      • Terasaki P.I.
      • et al.
      Treatment of lymphopenic hypogammaglobulinemia and bone-marrow aplasia by transplantation of allogeneic marrow. Crucial role of histocompatibility matching.
      in Minneapolis, demonstrated reactivity to the patient's cells in all 4 sisters; however, 1 sister (sister 3) clearly had a weak reaction (Fig. 3). This sister was also ABO incompatible. Making sense of the histocompatibility testing results at that time was a source of considerable discussion and soul-searching, for a misinterpretation of the genetics or biology could result in fatal GVHD reaction: (1) the HLA antigens did not segregate and (2) they did not seem to correlate with the segregation of the MLC results. Only after it was appreciated several years later that 2 serologic loci (HLA-A and HLA-B) existed could a crossover between the 2 loci in the donor cells be postulated to explain the serologic typing.
      • Gatti R.A.
      • Meuwissen H.J.
      • Terasaki P.I.
      • et al.
      Recombination within the HL-A locus.
      And only when the Class II loci were localized proximal to the Class I region of the MHC on chromosome 6 could one postulate that the crossover between HLA-A and HLA-B in sister 3 would carry with it the Class II region shared between patient and donor on haplotype B (see Fig. 3).
      Figure thumbnail gr3
      Fig. 3Histocompatibility testing of an X-SCID patient and family members, using HLA serologic typing and unidirectional MLC. Note that segregation of both HLA haplotyping and MLC reactions were only understandable after a crossover between HLA-A and HLA-B loci was appreciated. Class II loci on haplotype B (asterisks) of the patient would have then segregated with the proximal portion of recombinant haplotype B in Sib3, who became the stem cell donor.
      (Data from Gatti RA, Meuwissen HJ, Terasaki PI, et al. Recombination within the HL-A locus. Tissue Antigens 1971;1(5):239–41.)
      Driven by the almost certain fatal outcome of the disease in this family without treatment, a decision was made to attempt the bone marrow transplant using the 8-year-old sister 3 as the donor.
      • Gatti R.A.
      • Meuwissen H.J.
      • Allen H.D.
      • et al.
      Immunological reconstitution of sex-linked lymphopenic immunological deficiency.
      Both peripheral blood and bone marrow (obtained from iliac crests and tibial bones) were collected from the donor. Peripheral blood was collected 48 hours before collecting the marrow so that a stem-cell–rich fraction of nucleated cells could be prepared by density gradient centrifugation using 5% dextran. The cells were resuspended in donor plasma. In contrast to what was being done for oncologic patients, the infusion of both peripheral blood (5 × 106 lymphocytes/mL) and marrow (total of 109 nucleated cells) was given intraperitoneally, primarily to avoid having to filter out bone spicules and thereby reduce the number of cells available for engraftment. (In today's terms, approximately 10 × 106 CD34+ cells were infused into the 7-kg infant, or 1.25 × 106 stem cells/kg.)
      One week after the cells were infused, GVHD symptoms appeared, involving the skin, gut, and liver. This was accompanied by a hemolytic anemia thought to be caused by donor/host ABO incompatibility. No immunosuppressive therapies were given because of concern that immunosuppressive drugs would impede stem cell engraftment and because of experimental evidence that a mild GVHD would subside. One week later, the high fever and rash disappeared, and engraftment ensued. Proliferative responses to mitogens normalized, delayed-type hypersensitivity reactions could be demonstrated for the first time, and a bone marrow aspirate showed that 25% of bone marrow cells could be identified as female (donor) by karyotyping.
      Despite this early success, 45 days later, the patient developed a severe aplastic anemia. It was speculated that this was GVHD reaction involving the marrow. Donor-specific cytotoxic antibodies were demonstrated. A second bone marrow infusion followed.
      • Meuwissen H.J.
      • Gatti R.A.
      • Terasaki P.I.
      • et al.
      Treatment of lymphopenic hypogammaglobulinemia and bone-marrow aplasia by transplantation of allogeneic marrow. Crucial role of histocompatibility matching.
      • Gatti R.A.
      • Good R.A.
      Follow-up of correction of severe dual system immunodeficiency with bone marrow transplantation.
      Within 2 weeks, the leukocyte counts improved, GVHD had subsided, and the proportion of erythrocytes with the host's group A type had begun to decline, shifting instead to the donor's group O blood type.
      • Gatti R.A.
      • Good R.A.
      Follow-up of correction of severe dual system immunodeficiency with bone marrow transplantation.
      Group O cells have persisted to date, and the patient remains cured from his SCID diagnosis. For the first time, both SCID and aplastic anemia had been corrected by bone marrow transplantation and new therapeutic options became available for these disorders. It is also important to recognize that this experience confirmed the proposed model that the central defect in SCID patients resided in their lack of pluripotent stem cells and not a defective thymic microenvironment. A 2-year posttransplant evaluation demonstrated not only a stable immunologic reconstitution but also the transfer of T-cell memory, as evidenced by positive skin tests to mumps, despite that the child had never had mumps; the donor had had mumps shortly before her cells were harvested for transplant.
      Bach and colleagues
      • Bach F.H.
      • Albertini R.J.
      • Joo P.
      • et al.
      Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome.
      described a 22-month-old boy who was engrafted with bone marrow from a sister to correct for Wiskott-Aldrich syndrome (WAS). In contrast to patients with SCID, patients with WAS have evidence of immunologic function. To overcome the potential for rejection, a conditioning regimen consisting of azathioprine (5 mg/kg) and prednisone (2 mg/kg) was given for 2 days before the transplant. In contrast to the SCID case, the marrow infusion (6.5 × 109) was given intravenously through a femoral line. The patient developed Staphylococcus aureus positive intravenous line sepsis and graft failure. A second bone marrow transplant was given 4 days later, consisting of donor-derived peripheral blood mononuclear cells (PBMCs). It was speculated that donor PBMCs induced the expansion of recipient lymphocytes against minor donor HLA antigens. These lymphocytes would be subsequently eliminated by successive doses of cyclophosphamide at specific intervals. The transplanted female marrow initially seemed to engraft successfully. Fifteen years later, the patient was noted to have full T-cell and partial B-cell chimerism but no evidence of hematopoietic engraftment and remained thrombocytopenic.
      • Meuwissen H.J.
      • Bortin M.M.
      • Bach F.H.
      • et al.
      Long-term survival after bone marrow transplantation: a 15-year follow-up report of a patient with Wiskott-Aldrich syndrome.

      The dark days and the drawing board

      Despite early enthusiasm, the reality was that transplantation for anything other than severe immunodeficiency seemed to be of limited clinical application. An excellent review of all bone marrow transplants attempted between 1939 to 1969 was carefully recorded by Mortimer Bortin.
      • Bortin M.M.
      A compendium of reported human bone marrow transplants.
      The cases included 73 patients with aplastic anemia, 84 with leukemia, 31 with malignant disease, and 15 with immunodeficiency. Radiation and chloramphenicol were the most important known causes for aplastic anemia. Sixty percent of patients with acute leukemias were children (<18 years). Seven percent of autopsies had pulmonary evidence of marrow emboli. Of 203 transplants, at the time the report was written, 152 patients had died. Taken together, in 125 patients (60%) there was no evidence of engraftment. Evidence of chimerism was recognized in 11. Only 3 patients survived (all were immunodeficient patients and included the 2 patients described earlier). Graft rejection, infection, and GVHD were the main causes of death.
      During the 1970s, donor selection, control of GVHD, and conditioning regimens became areas of intense research in preclinical models. MLCs were used for the selection of donors. Weak in vitro responses suggested good compatibility. However, as HLA typing improved, it became apparent that MLC assays were difficult to interpret and were less reliable than what was required for clinical application. Serological testing for HLA-class II antigens was instituted. By the turn of the century serology was largely replaced by molecular identification of histocompatibility antigens. By 1975, Thomas and colleagues
      • Thomas E.D.
      • Storb R.
      • Clift R.A.
      • et al.
      Bone-marrow transplantation (second of two parts).
      published the first of a 2-part medical progress report on bone marrow transplantation. In this excellent synopsis, the authors discussed animal studies, the status of histocompatibility testing, conditioning regimens, techniques for marrow collection, fractionation and infusion, and the level of supportive care necessary for successful bone marrow transplantation.
      • Gatti R.A.
      • Kemple K.
      • Schwartzmann J.
      • et al.
      HLA-D typing with lymphoblastoid cell lines. VI. Rationale and goals of data reduction.
      • Gatti R.A.
      • Kempner D.H.
      • Leibold W.
      The role of the MHC antigens in the mature and immature host.

      Decades of advances

      The 1980s and 1990s saw a rapid increase in the number of transplants performed; national and international bone marrow registries were created, and cord blood was recognized as a source of stem cells. T-cell depletion techniques were introduced for prevention of GVHD, as matched sibling donors were only available 25% of the time, whereas HLA-haploidentical or mismatched family members were readily available. Soybean lectin agglutination coupled with erythrocyte rosetting with sheep red blood cell was developed by Reisner and colleagues
      • Reisner Y.
      • Kapoor N.
      • Kirkpatrick D.
      • et al.
      Transplantation for severe combined immunodeficiency with HLA-A, B, D, DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells.
      and was used successfully in patients with SCID and subsequently in patients with leukemia. Since that time, this approach has allowed for the survival of many infants with SCID
      • O'Reilly R.J.
      • Keever C.A.
      • Small T.N.
      • et al.
      The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease.
      • Buckley R.H.
      • Schiff S.E.
      • Sampson H.A.
      • et al.
      Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation.
      • Dror Y.
      • Gallagher R.
      • Wara D.W.
      • et al.
      Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation.
      • Buckley R.H.
      • Schiff S.E.
      • Schiff R.I.
      • et al.
      Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.
      and continues to be used today in different centers around the world.
      Novel methods of T-cell depletion were developed, including counterflow centrifugal elutriation and fractionation on density gradients.
      • de Witte T.
      • Hoogenhout J.
      • de Pauw B.
      • et al.
      Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation.
      • Lowenberg B.
      • Wagemaker G.
      • van Bekkum D.W.
      • et al.
      Graft-versus-host disease following transplantation of ‘one log’ versus ‘two log’ T-lymphocyte-depleted bone marrow from HLA-identical donors.
      By 1981, the first clinical trial using antithymocyte globulin was reported.
      • Rodt H.
      • Kolb H.J.
      • Netzel B.
      • et al.
      Effect of anti-T-cell globulin on GVHD in leukemic patients treated with BMT.
      Subsequently monoclonal antibodies were used in vivo and ex vivo for the treatment of marrow grafts for malignancies and PID patients.
      • Filipovich A.H.
      • McGlave P.
      • Ramsay N.K.
      • et al.
      Treatment of donor bone marrow with OKT3 (PAN-T monoclonal antibody) for prophylaxis of graft-vs.-host disease (GvHD) in histocompatible allogeneic bone marrow transplantation (BMT): a pilot study.
      • Filipovich A.H.
      • McGlave P.B.
      • Ramsay N.K.
      • et al.
      Pretreatment of donor bone marrow with monoclonal antibody OKT3 for prevention of acute graft-versus-host disease in allogeneic histocompatible bone-marrow transplantation.
      • Martin P.J.
      • Hansen J.A.
      • Thomas E.D.
      Preincubation of donor bone marrow cells with a combination of murine monoclonal anti-T-cell antibodies without complement does not prevent graft-versus-host disease after allogeneic marrow transplantation.
      • Umiel T.
      • Daley J.F.
      • Bhan A.K.
      • et al.
      Acquisition of immune competence by a subset of human cortical thymocytes expressing mature T cell antigens.
      However, with the depletion of T cells, important complications were recognized. These complications were higher incidence of graft failures, delayed immune reconstitution, increased risk of Epstein-Bar virus–associated lymphoproliferative disease, and CMV reactivation, and the overall survival was not significantly improved as compared with non–T-cell-depleted bone marrow.
      • Ho V.T.
      • Soiffer R.J.
      The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation.
      When CD34 was recognized as a glycoprotein that helped to identify hematopoietic progenitor cells, their isolation from peripheral blood provided another stem cell source. These peripheral blood stem cells (PBSCs) are capable of forming colonies of granulocytes/macrophages, erythrocytes, and other multipotential or immature progenitors.
      • Krause D.S.
      • Fackler M.J.
      • Civin C.I.
      • et al.
      CD34: structure, biology, and clinical utility.
      The introduction of growth factors such as granulocyte colony-stimulating factor(filgrastim) and granulocyte/macrophage colony-stimulating factor (sargramostim), plerixafor
      • Cashen A.F.
      Plerixafor hydrochloride: a novel agent for the mobilization of peripheral blood stem cells.
      (a novel molecule that inhibits chemokine receptor CXCR4 binding to stromal cell–derived factor-1), and other agents
      • Greinix H.T.
      • Worel N.
      New agents for mobilizing peripheral blood stem cells.
      have contributed to successful mobilization of CD34+ cells into the peripheral circulation and thus their use as a source of hematopoietic stem cells (HSCs). These PBSCs permitted high-dose salvage therapy to patients with refractory malignancies, resulting in prolonged survival and impeding tumor progression.
      • Kessinger A.
      • Armitage J.O.
      • Smith D.M.
      • et al.
      High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma.
      Although PBSCs have become a common source of HSCs for autologous transplants, their role in allogeneic transplants is still unclear.
      • Pidala J.
      • Anasetti C.
      • Kharfan-Dabaja M.A.
      • et al.
      Decision analysis of peripheral blood versus bone marrow hematopoietic stem cells for allogeneic hematopoietic cell transplantation.
      • Gallardo D.
      • de la Camara R.
      • Nieto J.B.
      • et al.
      Is mobilized peripheral blood comparable with bone marrow as a source of hematopoietic stem cells for allogeneic transplantation from HLA-identical sibling donors? A case-control study.
      • Gorin N.C.
      • Labopin M.
      • Blaise D.
      • et al.
      Higher incidence of relapse with peripheral blood rather than marrow as a source of stem cells in adults with acute myelocytic leukemia autografted during the first remission.
      Use of PBSCs may be influenced by multiple factors, including preference of the transplant center, primary disease, risk of relapse, graft-versus-leukemia effect, and donor preference. Experience with PBSCs for transplantation in patients with PID is limited.
      Umbilical cord blood (UCB) represents another alternative source of HSCs and has become a standard option for both children and adults with hematopoietic disorders and malignancies.
      • Gluckman E.
      • Broxmeyer H.A.
      • Auerbach A.D.
      • et al.
      Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling.
      • Gluckman E.
      • Rocha V.
      • Boyer-Chammard A.
      • et al.
      Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group.
      The advantages include (1) a low rate of viral contamination, (2) lower rates of GVHD, and (3) readily available units.
      • Gluckman E.
      • Rocha V.
      Cord blood transplantation: state of the art.
      The use of UCB for PID is limited. However 2 single-center experiences have been reported.
      • Knutsen A.P.
      • Wall D.A.
      Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience.
      • Bhattacharya A.
      • Slatter M.A.
      • Chapman C.E.
      • et al.
      Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency.
      In both series, immunologic reconstitution was demonstrated.
      Another promising methodology for HSCT would be to downregulate HLA expression by genetically engineering donor cells, using RNA interference (RNAi). This enables the cells to evade immune recognition.
      • Hacke K.
      • Falahati R.
      • Flebbe-Rehwaldt L.
      • et al.
      Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation.
      By integrating RNAi into genomic DNA, a universally accepted and expandable pool of donor cells would become available.

      Current status of SCT for PID

      There is no doubt that, for the past 4 decades, allogeneic SCT for PID has allowed for survival of patients in whom the natural history of the disease predicted an early death. The Center for International Blood and Marrow Transplant Research (CIBMTR) collects data in collaboration with the European Groups for Blood and Marrow Transplantation (EBMT), the Asia-Pacific Blood Marrow Transplant group (APBMT), and the World Marrow Donor Association (WMDA) along with transplants performed in North and South America. A progress report of comprehensive data as of 2008 is available, including more than 1500 transplants performed around the world for patients with SCID and other PIDs.
      The Medical College of Wisconsin and The National Marrow Donor Program. Center for International Blood and Marrow Transplant Research (CIBMTR).
      SCID represents the group of patients for whom HSCT is now considered standard of care; indeed, this PID has achieved the most successful survival record ranging from 63% to 100% when an HLA-matched sibling donor is available and 50% to 77% when haploidentical or HLA-mismatched donors are used.
      • Buckley R.H.
      • Schiff S.E.
      • Schiff R.I.
      • et al.
      Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.
      • Fischer A.
      • Landais P.
      • Friedrich W.
      • et al.
      Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency.
      • Antoine C.
      • Muller S.
      • Cant A.
      • et al.
      Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99.
      • Patel N.C.
      • Chinen J.
      • Rosenblatt H.M.
      • et al.
      Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAb.
      • Haddad E.
      • Landais P.
      • Friedrich W.
      • et al.
      Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.
      • Roifman C.M.
      • Grunebaum E.
      • Dalal I.
      • et al.
      Matched unrelated bone marrow transplant for severe combined immunodeficiency.
      • Grunebaum E.
      • Mazzolari E.
      • Porta F.
      • et al.
      Bone marrow transplantation for severe combined immune deficiency.
      • Railey M.D.
      • Lokhnygina Y.
      • Buckley R.H.
      Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis.
      • Mazzolari E.
      • Forino C.
      • Guerci S.
      • et al.
      Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency.
      The lack of donor availability, variable evidence of long-term immunologic reconstitution, and other limitations have led to the extensive use of unrelated but matched donors as a source of stem cells for SCID. The outcomes have improved over the recent years, with survivals ranging from 63% to 80%.
      • Antoine C.
      • Muller S.
      • Cant A.
      • et al.
      Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99.
      • Roifman C.M.
      • Grunebaum E.
      • Dalal I.
      • et al.
      Matched unrelated bone marrow transplant for severe combined immunodeficiency.
      • Grunebaum E.
      • Mazzolari E.
      • Porta F.
      • et al.
      Bone marrow transplantation for severe combined immune deficiency.
      • Mazzolari E.
      • Forino C.
      • Guerci S.
      • et al.
      Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency.
      • Rao K.
      • Amrolia P.J.
      • Jones A.
      • et al.
      Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen.
      The largest groups of non-SCID patients with primary immunodeficiencies for which SCT has been successful include WAS and chronic granulomatous disease. A collaborative study of the International Bone Marrow Transplant registry analyzed 170 transplants performed for WAS between 1968 and 1996. The overall 5-year probability of survival was 70% (95% confidence interval [CI], 63%–77%). Best outcomes were noted for patients receiving transplants from an HLA-identical sibling, 87% (95% CI, 74%–93%) as compared with 52% (95% CI, 37%–65%) for those receiving from other related donors. Matched unrelated donor transplants demonstrated a 5-year probability of survival of 71% (95% CI, 58%–80%). Of interest, if children receiving matched unrelated donor transplants were transplanted before the age of 5 years, the outcome was similar to HLA-matched sibling transplants.
      • Filipovich A.H.
      • Stone J.V.
      • Tomany S.C.
      • et al.
      Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program.
      A more recent long-term outcome analysis for patients who underwent transplant for WAS was performed by the European Society for Immunodeficiencies (ESID) and the EBMT.
      • Ozsahin H.
      • Cavazzana-Calvo M.
      • Notarangelo L.D.
      • et al.
      Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation.
      Included in the study were patients who had survived at least 2 years after HSCT. Survival was similar: 7-year event-free survival of 75%. Yet, a 20% incidence of autoimmunity was associated with mixed chimerism, independent of chronic GVHD. Furthermore, infection related to splenectomy was identified as an iatrogenic complication.
      • Ozsahin H.
      • Cavazzana-Calvo M.
      • Notarangelo L.D.
      • et al.
      Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation.
      Chronic granulomatous disease, an inherited disease of neutrophil function, is conventionally treated with prophylactic antibiotics and/or interferon therapy.
      The International Chronic Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group.
      However, long-term follow-up data suggest significant morbidity caused by infection and only 50% to 55% survival through the third and forth decades of life.
      • Liese J.
      • Kloos S.
      • Jendrossek V.
      • et al.
      Long-term follow-up and outcome of 39 patients with chronic granulomatous disease.
      • Jones L.B.
      • McGrogan P.
      • Flood T.J.
      • et al.
      Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry.
      HSCT has been a therapeutic option for the past 2 decades.
      • Di Bartolomeo P.
      • Di Girolamo G.
      • Angrilli F.
      • et al.
      Reconstitution of normal neutrophil function in chronic granulomatous disease by bone marrow transplantation.
      • Schettini F.
      • De Mattia D.
      • Manzionna M.M.
      • et al.
      Bone marrow transplantation for chronic granulomatous disease associated with cytochrome B deficiency.
      In 2002, the EBMT group reported results of 27 transplants from 1985 to 2000. Almost all (22 of 23) patients survived. These patients had received a myeloablative busulfan-containing conditioning regimen from an HLA-identical donor and achieved full and stable donor chimerism.
      • Seger R.A.
      • Gungor T.
      • Belohradsky B.H.
      • et al.
      Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985–2000.
      More recently, excellent survival (90%) after HSCT has been reported by the Newcastle group, with a median 61 months of follow-up.
      • Soncini E.
      • Slatter M.A.
      • Jones L.B.
      • et al.
      Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth.
      Disorders such as X-linked lymphoproliferative syndrome,
      • Hoffmann T.
      • Heilmann C.
      • Madsen H.O.
      • et al.
      Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP).
      the familial forms of hemophagocytic lymphohistiocytosis,
      • Jordan M.B.
      • Filipovich A.H.
      Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step.
      leukocyte adhesion deficiency,
      • Qasim W.
      • Cavazzana-Calvo M.
      • Davies E.G.
      • et al.
      Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency.
      CD40 ligand deficiency,
      • Isam H.
      • Al-Wahadneh A.
      Successful bone marrow transplantation in a child with X-linked hyper-IgM syndrome.
      • Duplantier J.E.
      • Seyama K.
      • Day N.K.
      • et al.
      Immunologic reconstitution following bone marrow transplantation for X-linked hyper IgM syndrome.
      and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
      • Rao A.
      • Kamani N.
      • Filipovich A.
      • et al.
      Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning.
      are within the spectrum of diseases treated with HSCT. Patients with Chédiak-Higashi syndrome have also been treated with HSCT; however, late-onset cognitive impairment has been described 20 years posttransplant.
      • Tardieu M.
      • Lacroix C.
      • Neven B.
      • et al.
      Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome.

      Summary

      The last 40 years has seen the emergence of HSCT as a therapeutic modality for fatal diseases and as a curative option for individuals born with inherited disorders that carry limited life expectancy and poor quality of life. Despite the rarity of many PIDs, these disorders have led the way toward innovative therapies and further provide insights into mechanisms of immunologic reconstitution applicable to all HSC transplants. Critical analysis of outcomes and prospective multicenter clinical trials will be necessary to further our understanding as to best therapeutic approaches for patients with PID, who constitute a very heterogenous group of patients.

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