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Biomedical subjects

M J Cowan

Publications and source records attributed to M J Cowan.

At least 19 recordsLinked to original sources
PubMed1998

Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group.

Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

Bone Marrow Transplantation↗
PubMed1998

The gene for severe combined immunodeficiency disease in Athabascan-speaking Native Americans is located on chromosome 10p.

Severe combined immunodeficiency disease (SCID) consists of a group of heterogeneous genetic disorders. The most severe phenotype, T-B- SCID, is inherited as an autosomal recessive trait and is characterized by a profound deficiency of both T cell and B cell immunity. There is a uniquely high frequency of T-B- SCID among Athabascan-speaking Native Americans (A-SCID). To localize the A-SCID gene, we conducted a genomewide search, using linkage analysis of approximately 300 microsatellite markers in 14 affected Athabascan-speaking Native American families. We obtained conclusive evidence for linkage of the A-SCID locus to markers on chromosome 10p. The maximum pairwise LOD scores 4.53 and 4.60 were obtained from two adjacent markers, D10S191 and D10S1653, respectively, at a recombination fraction of straight theta=.00. Recombination events placed the gene in an interval of approximately 6.5 cM flanked by D10S1664 and D10S674. Multipoint analysis positioned the gene for the A-SCID phenotype between D10S191 and D10S1653, with a peak LOD score of 5.10 at D10S191. Strong linkage disequilibrium was found in five linked markers spanning approximately 6.5 cM in the candidate region, suggesting a founder effect with an ancestral mutation that occurred sometime before 1300 A.D.

Alleles↗
PubMed1997

Recruitment of engrafted donor cells postnatally into the blood with cytokines after in utero transplantation in mice.

BACKGROUND: We have previously shown that MHC-mismatched fetal liver cells can durably engraft in 45% of nondefective fetal mice, although male donor cells were found in the blood in only 8% of female recipients. We postulated that adult bone marrow stem cells would engraft similarly to fetal liver cells and that postnatal administration of cytokines would recruit donor cells into the peripheral circulation. METHODS: Bone marrow from C57BL/6 adult male mice was injected into allogeneic BALB/c or congenic C57BL/6 fetal recipients that were 11-13 days old. Engraftment was tested by quantitative polymerase chain reaction for the Y chromosome in female recipients (0.0001% sensitivity). Recipients were injected at 1-2 years of age with rat stem cell factor (SCF) and human granulocyte colony-stimulating factor (G-CSF) for 7 days and tested for donor cells in the blood. RESULTS: The overall engraftment rate (in the blood, spleen, or liver) was 44% in both female allogeneic and congenic bone marrow recipients. Of 49 recipients of bone marrow or fetal liver cells with no evidence of donor cells in the blood before injection, 29 (59%) developed circulating donor cells at some time after cytokine injection for up to 2 months. Twenty-seven of 49 animals were negative in the blood, liver, and spleen before cytokine therapy; 14 of 27 (52%) became positive in the blood after stem cell factor/granulocyte colony-stimulating factor injection. Tolerance to donor skin grafts was not altered by the mobilization of donor cells into the circulation. CONCLUSIONS: Adult bone marrow durably engrafts in nondefective mice at a rate similar to that previously obtained with fetal liver. Engrafted donor cells can be mobilized with cytokines into the circulation for up to 2 months even in animals with no evidence of donor cells in the blood, liver, or spleen. Based on these results we estimate that 70-75% of hematopoietically nondefective fetal mice engraft with MHC-mismatched fetal liver or adult bone marrow stem cells.

Animals↗
PubMed1997

In utero hematopoietic stem cell transplants prolong survival of postnatal kidney transplantation in monkeys.

The authors hypothesized that in utero transplantation of T-cell-depleted paternal marrow into rhesus monkey fetuses would induce tolerance to postnatal kidney grafts from the marrow donor. T-cell-depleted paternal bone marrow was transplanted intraperitoneally into two female fetal rhesus monkeys at 61 +/- 1 days' gestation. Chimeric monkeys (n = 2) received kidney transplants from paternal donors. Control monkeys (n = 2) underwent kidney transplants without prior in utero stem cell transplants. Both chimeric monkeys demonstrated low level (<0.1% donor cells) engraftment in the bone marrow and peripheral blood using the polymerase chain reaction assay for the Y chromosome. The mixed lymphocyte reaction demonstrated hyporeactivity to the donor. Control animals demonstrated severe acute rejection and graft failure 1 week posttransplant. The first chimeric monkey had no significant clinical or sonographic evidence of renal failure until 7 weeks after the transplant. Biopsy findings showed mild rejection 1 week postoperatively, but rejection did not significantly progress until 5 weeks later. The second chimeric monkey had no significant clinical or sonographic changes for 4 weeks, but evidence of moderate rejection was seen on biopsy results. This monkey was given a 10-week course of immunosuppression, and had no clinical or sonographic renal deterioration, although biopsy results showed chronic rejection that was confirmed when electively euthanized 8 months later. Our data suggest that in utero transplantation of hematopoietic stem cells can increase the survival of a kidney allograft in the rhesus monkey.

Animals↗
PubMed1997

Acute respiratory failure in the HIV-seropositive patient.

Since approximately 40% to 65% of patients with AIDS will develop pulmonary disease, HIV-seropositive patients represent a large cohort of immunosuppressed individuals with the potential to progress to respiratory failure requiring mechanical ventilation and admission to the intensive care unit. This article reviews the cause, pathophysiology, diagnostic approach, and management of acute respiratory failure requiring mechanical ventilation in HIV-seropositive patients. Prognostic factors and survival rates for episodes of respiratory failure are also discussed. In addition, an overview of acute respiratory failure in pediatric AIDS patients is presented.

Adolescent↗
PubMed1997

Maternal mosaicism for a novel interleukin-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency in a Navajo kindred.

X-linked severe combined immunodeficiency disease (SCID) results from mutations of IL2RG, the gene encoding the interleukin-2 receptor gamma chain, also known as the common gamma chain (gamma c). A distinct form of autosomal recessive SCID occurs at an increased frequency among the Navajo Native American population. The disease gene responsible for autosomal Navajo SCID remains to be determined. We report the occurrence of X-linked SCID in a Navajo Native American kindred with two affected brothers. X-linked SCID was suggested by the presence of circulating B cells and the absence of surface gamma c expression in a cell line derived from an affected male. A C-to-T transition was demonstrated in exon 5 of the IL2RG gene, resulting in the substitution of tryptophan for arginine at position 224. This change was not present in the peripheral blood lymphocytes of the mother, thus proving the occurrence of a new mutation in the maternal germline. This report underscores the importance of establishing a specific genetic diagnosis for SCID cases and illustrates the inherent difficulties in providing genetic counseling in cases involving mosaicism.

Female↗
PubMed1997

Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation.

Children receiving a bone marrow transplant (BMT) are at risk for neuropsychological late effects because of potentially neurotoxic chemotherapy and total body irradiation. The goal of this study was to prospectively and longitudinally assess the intellectual and adaptive functioning of children receiving a BMT. This study examined 67 children whose development was evaluated at baseline prior to BMT and at 1 year follow-up. Mean age at BMT was 45 months. Repeated-measures ANOVA indicated a significant decline in IQ between baseline and the 1 year follow-up evaluation. Multivariate and exploratory univariate analyses examined the potential influence of diagnosis, treatment regimen, cranial radiation dose, age at time of transplant, and sex of child but none of these independent variables predicted outcome. Twenty-six children (mean age at BMT of 28.4 months) were also given developmental evaluations 3 years post-BMT. Although IQ at the 1 year follow-up was significantly lower than baseline, no further changes were evident at the 3 year follow-up evaluation. Scores on the Vineland Adaptive Behavior Scales also dropped significantly between baseline and the 1 year follow-up, but did not change between the 1 year and 3 year evaluations.

Adaptation, Psychological↗
PubMed1997

Bone marrow transplantation for inherited diseases.

Allogeneic bone marrow transplantation has been used successfully for the treatment of a variety of inherited diseases. The goal of transplantation in this setting is to provide a sufficient degree of sustained marrow engraftment to allow longterm amelioration of the inherited disease phenotype. Many factors influence the likelihood of achieving this goal, including donor availability, conditioning regimen, marrow processing, and the nature and extent of progression of the disease. For many inherited diseases early diagnosis is imperative because the outcome of transplantation is more favorable when performed prior to the development of significant organ damage from the disease, its complications, or treatment. Although the results of bone marrow transplantation are good for some inherited diseases and are improving for others, significant problems remain such as donor availability, conditioning regimen toxicity, graft failure, and graft-versus-host disease. This review describes some of the unique features of bone marrow transplantation for inherited diseases and discusses recent advances in this area.

Anemia, Sickle Cell↗
PubMed1997

Psychosocial consequences of bone marrow transplantation in donor and nondonor siblings.

We investigated the psychosocial effects of bone marrow transplantation (BMT) on siblings of transplant recipients. We asked how donor siblings compared with nondonor siblings on quantitative measures of behavior, psychological distress, and sense of self. Participants included 44 siblings (21 donors and 23 nondonors, ages 6-18 yr) of surviving pediatric BMT patients. On self-report measures, donors reported significantly more anxiety and lower self-esteem than nondonors. On teacher-rated scales, donors showed significantly more adaptive skills in school. On these same scales, nondonors showed significantly more school problems than donors. One-third of the siblings in each group reported a moderate level of post-traumatic stress reaction. Exploratory multiple regression analyses point to factors that might influence sibling adjustment and suggest counseling strategies and avenues for future research.

Adaptation, Psychological↗
PubMed1996

Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome.

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

Bone Marrow Transplantation↗
PubMed1996

A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to haemophilus influenzae type b disease.

The antibody response to H. influenzae type b (Hib) is pauciclonal, and is dominated by antibodies using the VkappaA2 gene. Navajos have a 5-10-fold increased incidence of Hib disease compared with control populations. We hypothesized that a polymorphism in one of the genes in this oligoclonal response may lead to increased disease susceptibility. Since the predominant A2+ anti-Hib antibodies have high avidity for Hib and can be unmutated, the A2 Vkappa gene was analyzed. Over half of the Navajos studied, but only one control individual, had a new allele of A2, termed A2b, with three changes from the published A2 germline sequence. One of the changes was in the recombination signal sequence, suggesting that the A2b allele might not undergo V-J rearrangement very frequently. This possibility was confirmed by analyzing the relative frequency of non-productive A2 rearrangements in A2a/b heterozygous Navajos. Many fewer A2b rearrangements were observed, showing that the A2b allele is defective in its ability to undergo rearrangement. The prevalence of this allele in Navajos may play a role in their increased susceptibility to invasive Hib disease. If so, it would underscore the importance of the germline Ig repertoire for protective antibody responses to pathogenic bacteria in unimmunized children.

Alleles↗
PubMed1996

Toxicities of total-body irradiation for pediatric bone marrow transplantation.

PURPOSE: To determine the acute and late effects, including cognitive function, of total body irradiation (TBI) and chemotherapy for bone transplant (BMT) in children with immunodeficiency or hematologic disorders. METHODS AND MATERIALS: At UCSF, 15 children with immunodeficiency disorders and 58 children with leukemia received chemoradiotherapy between July 1982 and November 1993 and were evaluated for toxicity. Patients with severe combined immunodeficiency disorder (SCID) received 7 Gy TBI while leukemia patients received 12 Gy TBI. RESULTS: Eight immunodeficient patients (53%) are alive at 4 months to 11 years posttransplant. Acute toxicity was limited and treatment well tolerated. Most patients developed mild nausea and vomiting, skin rash, or erythema. Transient fever/chills, oral mucositis, and alopecia were noted in approximately 50% of patients. Seventy-three percent of all patients demonstrated acute liver dysfunction, but only four (27%) developed veno-occlusive disease. All children had decreased growth velocity but normal growth hormone levels. Other endocrinologic evaluations including adrenocorticotropic hormone (ACTH), cortisol, and thyroid hormones were normal. Only one evaluable girl had delayed puberty with late onset of secondary sexual characteristics. Neuropsychological testing demonstrated an intelligence quotient (IQ) reduction between the baseline and 1 year post-BMT, with some recovery at 3 years. Only one patient developed a clinically significant cataract. Thirteen percent of patients had chronic interstitial lung disease. Four children developed exostosis. Only 1 of the 15 children developed a second malignancy (acute myelogenous leukemia) at age 5, 51 months posttransplant for SCID. For patients with leukemia, similar toxicities were observed. Twenty-nine percent disease-free survival was noted with a mean follow-up of 4.7 years. Twenty-two percent had chronic interstitial lung disease and two patients were diagnosed with cataracts. Graft-vs.-host-disease (GVHD), pubertal development arrest, and delayed puberty were seen. One child developed papillary thyroid carcinoma, 49 months post-BMT. Similar neuropsychological testing decrements were also observed. CONCLUSION: Our experience suggests that intensive chemoradiotherapy, even at a young age, does not cause severe, acute, or late toxicities but does result in a small IQ decrement and the risk of secondary malignancy in children with long-term follow-up.

Adolescent↗
PubMed1996

Circulating red cells usually remain of host origin after bone marrow transplantation for severe combined immunodeficiency.

BACKGROUND: Patients with severe combined immunodeficiency (SCID) treated with allogeneic bone marrow transplantation often receive a milder conditioning regimen than patients who undergo transplantation for hematologic malignancy, and they regularly retain circulating white cells of host origin. The origin of circulating red cells following successful bone marrow transplantation to treat SCID is not known. STUDY DESIGN AND METHODS: Review of the medical records identified all patients with SCID who underwent ABO-mismatched bone marrow transplantation at the University of California, San Francisco, between 1982 and 1994. The ABO and Rh phenotype at >6 months after transplantation was determined for all successful transplants by review of the medical record or the taking of a fresh blood sample for analysis. Patient-conditioning and donor bone marrow-preparative regimens were reviewed to assess their possible influence on the red cell phenotype after successful bone marrow transplantation. RESULTS: Nine of 35 SCID patients who underwent successful transplantation received marrow from ABO-mismatched donors. Eight of the nine patients had only host red cells circulating at 6 to 84 months after transplantation, while one patient had only donor red cells circulating at 48 months after transplantation. None of the patients had circulating red cells of both host and donor origin. Conditioning regimens included cyclophosphamide and antithymocyte globulin for all nine patients; only three patients also received total body irradiation. Seven of the nine patients received related-donor, HLA-mismatched bone marrow, and two patients received HLA-identical bone marrow; eight patients received T-cell-depleted bone marrow. The one patient whose red cell phenotype converted to that of the donor received T-cell-depleted, haploidentical marrow, and the preparative regimen included chemotherapy and total body irradiation. CONCLUSION: SCID patients successfully treated with allogeneic bone marrow transplantation typically fail to show circulating red cells of donor phenotype; this finding is in contrast to the universal presence of circulating donor red cells following successful bone marrow transplantation to treat hematologic malignancies and other diseases. The milder conditioning regimens typically given to patients with SCID, along with T-cell depletion and HLA mismatching, may play a role in this different outcome. It is not known whether the inability to find circulating red cells of donor origin is due to a failure to engraft donor pluripotent stem cells or a failure of engrafted donor stem cells to differentiate along the erythroid lineage.

Blood Grouping and Crossmatching↗
PubMed1996

New alleles of IGKV genes A2 and A18 suggest significant human IGKV locus polymorphism.

The human kappa light chain consists of approximately 35 potentially functional IGKV genes. However, an estimation of the diversity in the IGKV repertoire of an individual will be affected by the extent of polymorphisms for the different IGKV genes and their patterns of inheritance. To date, little information is available to indicate the extent of allelic variation of the IGKV genes. We examined the extent of allelism for one IGKV gene pair, the distal region A2 gene and its closely related proximal region duplicate A18. We found two new alleles for A2 and one new allele for A18, and sequenced approximately 1 kilobase flanking each gene. The new A18 allele, unlike the originally described allele, appears to be functional. All these alleles were found at relatively high frequencies in the four ethnic populations studied, with the exception of the defective A2b allele which was highly represented only in Navajos. The originally described A2a allele encodes for the predominant protective antibody against Haemophilus influenzae. Therefore, the patterns of allelic inheritance described for this IGKV gene pair indicate that allelism in the IGKV locus is likely to have a significant impact on immune responses.

Alleles↗
PubMed1996

Bone marrow 'boosts' following T cell-depleted haploidentical bone marrow transplantation.

Nine patients transplanted for non-malignant conditions (eight severe combined immunodeficiency, one aplastic anemia) received lectin-treated T cell-depleted BMTs from haploidentical donors. Each patient subsequently received a second T cell-depleted transplant (¿boost') from the same donor, without conditioning, because of a delay in the recovery of T cell immunity associated with evidence of engraftment. The median time to boost after initial BMT was 0.5 years (range 0.2-4.6 years). No conditioning therapy was used prior to the boost (except one patient who received ATG) and no GVHD prophylaxis was used during either the initial or subsequent BMTs. Eight of the nine patients are surviving at a median follow-up of 2.9 years (range 0.3-6.2 years). Following BMT boost, T cell function improved with the lymphocyte proliferative responses to PHA, PWM and alloantigen all increasing at least eight-fold. The mean percentage of CD3+ lymphocytes increased from 20 +/- 7% of total lymphocytes following the first BMT to 66 +/- 7% following the marrow boost (P < 0.001). This increase was generated primarily by an increase in the CD4+ lymphocyte subset which increased from 13 +/- 3% post-transplant to 44 +/- 6% after the BMT boost (P < 0.005), and was reflected in both the CD4+/Leu8+ and CD4+/Leu8- lymphocyte populations. Measurements of B cell immunity (immunoglobulins, isohemagglutinins and B cells) showed no significant effect of the marrow boosts. These results suggest that bone marrow 'boosts' are an effective means for improving T cell immunity in patients who fail to recover adequate immune function after T cell-depleted bone marrow transplantation and may be applicable as immunotherapy following allogeneic BMT undertaken to treat malignancy.

Anemia, Aplastic↗
PubMed1996

Long-term engraftment following in utero T cell-depleted parental marrow transplantation into fetal rhesus monkeys.

A major concern with allogeneic BMT for treating most inherited diseases is the need to overcome graft rejection with conditioning chemotherapy which is associated with a relatively high morbidity and mortality. This can be eliminated if the transplant is done in utero when the fetus is unable to reject donor hematopoietic stem cells (HSC). We studied the efficacy of T cell-depleted (TCD) parental bone marrow as a source of HSC for transplantation into early gestation non-defective fetal rhesus monkeys. Thirteen opposite sexed TCD transplants were done into 44 day fetal recipients and 12 into 61 day recipients (165 day total gestation). The procedure-related mortality was 8%, all in the earlier age group. The overall survival was 60% at birth with a projected survival of 44 +/- 10% at 1.5 years with no difference between the two age groups. We used a PCR assay for the rhesus Y chromosome to detect male donor cells in female recipients (six animals transplanted at 44 days and five at 63 days). The overall engraftment rate was 73% with no difference as a function of gestational age at transplant. In six long-term surviving engrafted females we detected donor cells in the peripheral blood and bone marrow up to 3 years of age. We found a delay in the appearance of donor cells in the peripheral blood in engrafted animals, in some cases for up to 6 months post-BMT. In vitro mixed lymphocyte reaction and cell-mediated lymphocytotoxicity studies between the recipient and donor cells indicate that tolerance was induced to donor cells. Individual and pooled erythroid and myeloid marrow colonies grown in methyl cellulose were collected and analyzed for donor origin by PCR. The amount of donor cells in marrows from long-term engrafted animals was < 0.1%. In a fetal recipient studied at 35 days post-BMT, donor cells were detected in bone marrow and liver in both erythroid and myeloid lineages. These results indicate that TCD parental marrow can durably engraft in utero. While the engraftment rate is similar to that seen with fetal liver as the source of HSC, the degree of peripheral blood engraftment (percent donor cells) in this non-defective primate model is low. It will require increasing the percent pre-or postnatally for this approach to be clinically relevant in those disorders in which there is no selective survival advantage for normal engrafted donor cells.

Animals↗
PubMed1996

Haploidentical bone marrow transplants for two patients with reticular dysgenesis.

We report two cases of reticular dysgenesis (RD) successfully treated by BMT utilizing T cell-depleted haploidentical marrow grafts. One child failed to engraft after conditioning with ATG, and the other failed two transplant attempts with cyclophosphamide + ATG, and busulfan + cyclophosphamide + ATG, respectively. Donor engraftment was achieved in both patients following treatment with 700 cGy TBI, with or without other agents. These results, taken together with previous reports in the literature, suggest that children with RD may require more intensive conditioning than patients with other types of severe combined immunodeficiency syndrome.

Agranulocytosis↗