Arati Raziuddin

Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

Background The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. Methods All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. Results In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10 000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)—a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). Conclusion This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.

Immunobiology of natural killer cells and bone marrow transplantation: merging of basic and preclinical studies

Summary: Natural killer (NK) cells mediate acute rejection of bone marrow, but not solid tissue, allografts in lethally irradiated mice. Precisely how and why this rejection occurs is still unclear. In allogeneic bone marrow transplantation (BMT), a spectrum of results is possible; one result can be marrow graft failure due to host rejection of the graft by NK and T cells and, at the opposite spectrum, the occurrence of graft‐versus‐host disease (GVHD). Donor NK cells, however, appear capable of improving donor engraftment without giving rise to GVHD and thus may be of use as an immunotherapy following BMT. As NK‐cell inhibitory receptors play a role in bone marrow cell rejection, these same inhibitory receptors may also affect NK responses towards tumor cells. It has been demonstrated that blocking the interaction of inhibitory receptors with MHC determinants on tumor cells can result in greater antitumor effects. Thus, NK cells are capable of mediating both positive and negative effects during BMT depending on whether they are of host versus donor origin and their state of activation. Understanding their role in BMT provides insights as to their physiological roles and points the way to potential clinical uses.

Recombinant Human Growth Hormone Promotes Hematopoietic Reconstitution after Syngeneic Bone Marrow Transplantation in Mice

Recombinant human growth hormone (rhGH) was administered to mice after syngeneic bone marrow transplantation (BMT) to determine its effect on hematopoietic reconstitution. BALB/c mice were given 10 μg intraperitoneal injections of rhGH every other day for a total of 10 injections following syngeneic BMT. Mice that received rhGH exhibited significant increases in total hematopoietic progenitor cell content (colony‐forming unit‐culture) in both bone marrow and spleen. Erythroid cell progenitor content (burst‐forming unit‐erythroid) was also significantly increased after rhGH treatment. Analysis of peripheral blood indicated that administration of rhGH resulted in significant increases in the rate of white blood cell and platelet recovery. Granulocyte marker 8C5+ cells were also increased in the bone marrow and spleens of treated mice. Red blood cell, hematocrit, and hemoglobin levels were increased at all time points after rhGH treatment. No significant pathologic effects or weight gain were observed in mice receiving repeated injections of 10 μg rhGH. Thus, rhGH administration after syngeneic BMT promoted multilineage hematopoietic reconstitution and may be of clinical use for accelerating hematopoiesis after autologous BMT.

Prolactin exerts hematopoietic growth-promoting effects in vivo and partially counteracts myelosuppression by azidothymidine

Prolactin (PRL) is a neuroendocrine hormone that influences immune and hematopoietic development. The mechanism of action of this hormone in vivo remains unclear; therefore, we assessed the effects of PRL on hematopoiesis in vivo and in vitro. Normal resting mice were treated with 0, 1, 10, or 100 microg of recombinant human prolactin (rhPRL) for 4 consecutive days and euthanized on the fifth day for analysis of myeloid and erythroid progenitors in the bone marrow and spleen. Both frequencies and absolute numbers of splenic colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-e) were significantly increased in mice receiving rhPRL compared to the controls that had received saline only. Bone marrow cellularities were not significantly affected by any dose of rhPRL, but the absolute numbers and frequencies of bone marrow CFU-GM and BFU-e were augmented by rhPRL. These results suggest that rhPRL can promote hematopoiesis in vivo. Because rhPRL augments myeloid development in vivo, we examined the potential of the hormone to reverse the anemia and myelosuppression induced by azidothymidine (AZT). Mice were given rhPRL injections concurrent with 2.5 mg/mL AZT in drinking water. rhPRL partially restored hematocrits in the animals after 2 weeks of treatment and increased CFU-GM and BFU-e in both spleens and bone marrow. The experiments with AZT and rhPRL support the conclusion that the hormone increases myeloid and erythroid progenitor numbers in vivo, and they suggest that the hormone is clinically useful in reversing myelosuppression induced by AZT or other myeloablative therapies.

Ly-49 receptor expression and functional analysis in multiple mouse strains

We present data on the strain distribution and functional characteristics of the Ly‐49 receptors A, C/I, D, and G2 on DX5+ natural killer (NK) cells. We have examined tyrosine phosphorylation of the Ly‐49 molecules, regulation of NK cytotoxic functions, and in vivo marrow rejection capability. The flow cytometry results demonstrate a diverse and complex pattern of expression of the Ly‐49 receptors in the 11 strains examined. The vast majority of NK cells express Ly‐49s, although some NK1.1+ CD3+ cells also express these receptors. The results of our functional analysis indicate that H‐2Dd was able to inhibit the function of Ly‐49G2+ NK cells, not only in B6 mice, but also by NK cells derived from several haplotypes. The examination of Ly‐49 receptor tyrosine phosphorylation, which is a biochemical measure of inhibitory function, was consistently observed in the 11 mouse strains examined. In contrast, analysis of Ly‐49D function suggests its expression appears to be more restricted and that H‐2Dd is an activating ligand for this receptor. In addition, the in vivo examination of both inhibitory (Ly‐49G2) and activating (Ly‐49D) receptors demonstrated regulatory roles of these class I binding receptors in marrow transplantation. J. Leukoc. Biol. 66: 512–520; 1999.