Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency.

BACKGROUND: Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. OBJECTIVE: We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. METHODS: We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n = 37) or MSDs (n = 66). RESULTS: Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P < .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versus-host disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients (P < .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P < .001). CONCLUSION: Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy.

Experimental cerebral malaria develops independently of endothelial expression of intercellular adhesion molecule-1 (icam-1).

Cerebral malaria (CM) is a severe clinical complication of Plasmodium falciparum malaria infection and is characterized by a high fatality rate and neurological damage. Sequestration of parasite-infected red blood cells in brain microvasculature utilizes host- and parasite-derived adhesion molecules and is an important factor in the development of CM. ICAM-1, an alternatively spliced adhesion molecule, is believed to be critical on endothelial cells for infected red blood cell sequestration in CM. Using ICAM-1 mutant mice, we found that the full-length ICAM-1 isoform is not required for development of murine experimental CM (ECM) and that ECM phenotype varies with the combination of ICAM-1 isoforms expressed. Furthermore, we observed development of ECM in transgenic mice expressing ICAM-1 only on leukocytes, indicating that endothelial cell expression of this adhesion molecule is not required for disease pathogenesis. We propose that ICAM-1-dependent cellular aggregation, independent of ICAM-1 expression on the cerebral microvasculature, contributes to ECM.

Adult T-cell leukemia/lymphoma in an adolescent presenting with skin lesions.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus-I. Adult T-cell leukemia/lymphoma is primarily a disease of adults due to the long latency period between initial infection and development of leukemia. We present a case of acute adult T-cell leukemia/lymphoma in an adolescent. Skin lesions had appeared 3 years earlier and were the initial sign of human T-cell lymphotropic virus-I infection and T-cell malignancy. Her disease failed to respond to both intensive chemotherapy and antiviral therapy. Cutaneous lesions are sometimes the initial sign of adult T-cell leukemia/lymphoma and early recognition is imperative.

G2E3 is a dual function ubiquitin ligase required for early embryonic development.

G2E3 is a putative ubiquitin ligase (E3) identified in a microarray screen for mitotic regulatory proteins. It shuttles between the cytoplasm and nucleus, concentrating in nucleoli and relocalizing to the nucleoplasm in response to DNA damage. In this study, we demonstrate that G2E3 is an unusual ubiquitin ligase that is essential in early embryonic development to prevent apoptotic death. This protein has a catalytically inactive HECT domain and two distinct RING-like ubiquitin ligase domains that catalyze lysine 48-linked polyubiquitination. To address in vivo function, we generated a knock-out mouse model of G2E3 deficiency that incorporates a beta-galactosidase reporter gene under control of the endogenous promoter. Animals heterozygous for G2E3 inactivation are phenotypically normal with no overt change in development, growth, longevity, or fertility, whereas G2E3 null embryos die prior to implantation. Although normal numbers of G2E3(-/-) blastocysts are present at embryonic day 3.5, these blastocysts involute in culture as a result of massive apoptosis. Using beta-galactosidase staining as a marker for protein expression, we demonstrate that G2E3 is predominantly expressed within the central nervous system and the early stages of limb bud formation of the developing embryo. In adult animals, the most intense staining is found in Purkinje cell bodies and cells lining the ductus deferens. In summary, G2E3 is a dual function ubiquitin ligase essential for prevention of apoptosis in early embryogenesis.

G2E3 is a nucleo-cytoplasmic shuttling protein with DNA damage responsive localization.

G2E3 was originally described as a G2/M-specific gene with DNA damage responsive expression. The presence of a conserved HECT domain within the carboxy-terminus of the protein indicated that it likely functions as a ubiquitin ligase or E3. Although HECT domains are known to function in this capacity for many proteins, we demonstrate that a portion of the HECT domain from G2E3 plays an important role in the dynamic subcellular localization of the protein. We have shown that G2E3 is a nucleo-cytoplasmic shuttling protein with nuclear export mediated by a novel nuclear export domain that functions independently of CRM1. In full-length G2E3, a separate region of the HECT domain suppresses the function of the NES. Additionally, G2E3 contains a nucleolar localization signal (NoLS) in its amino terminus. Localization of G2E3 to the nucleolus is a dynamic process, and the protein delocalizes from the nucleolus rapidly after DNA damage. Cell cycle phase-specific expression and highly regulated subcellular localization of G2E3 suggest a possible role in cell cycle regulation and the cellular response to DNA damage.