The role of human and viral cytokines in the pathogenesis of multiple myeloma.

Multiple myeloma (MM) is characterized by the accumulation of monoclonal plasma cells, a terminally differentiated form of B lymphocyte, in the bone marrow. This disease is most often associated with bone destruction, anemia and renal failure. Besides the malignant plasma cells, it has become clear that nonmalignant cells in the bone marrow also contribute to the development of this malignancy by the release of cytokines. Further support for the importance of the supporting cells comes from our recent finding of the human herpesvirus 8 (HHV-8) in the nonmalignant bone marrow stromal cells from these patients.

Human herpesvirus 8 open reading frame 26 and open reading frame 65 sequences from multiple myeloma patients: a shared pattern not found in Kaposi's sarcoma or primary effusion lymphoma.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, has been implicated in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease, and recently multiple myeloma (MM). DNA sequence analyses of HHV-8 suggest that multiple HHV-8 strains exist. We extracted DNA from 24 patients with MM and 3 patients with monoclonal gammopathy of undetermined significance and compared HHV-8 open reading frames (ORFs) 26 and 65 sequences with those derived from patients with KS, PEL, and two HHV-8-positive PEL cell lines KS-1 and BC-1. ORF26 sequence data suggest that MM patients are consistently carriers of HHV-8 strain subtype C3. All MM patients also consistently revealed either a single bp deletion or substitution at position 112197 in ORF65. This unique alteration is not present in patients with KS or PEL or in PEL cell lines. It occurs in the portion of ORF65 that is known to be responsible for a serological response to HHV-8.

Recent advances in multiple myeloma.

Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear. Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting. The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation.

HHV-8 infection and multiple myeloma.

Human herpes virus 8 (HHV-8) also known as Kaposi's sarcoma-associated herpes virus has been strongly implicated in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease. Recently, this gamma-herpes virus was also found in the nonmalignant bone marrow dendritic cells of the majority of myeloma patients. In addition, HHV-8 is also detectable in the peripheral blood of most myeloma patients. In contrast, this virus is rarely detected in close contacts of myeloma patients or healthy subjects. Furthermore, only about one-third of patients with monoclonal gammopathy of undetermined significance (MGUS) are infected with HHV-8. Sequencing of HHV-8 DNA isolated from myeloma patients shows both interpatient differences and conserved differences unique to myeloma compared to HHV-8 in other malignancies. Consistent expression of both the viral homologs of interferon regulatory factor and interleukin-8 receptor in myeloma suggests a possible role for these transforming viral genes in the pathogenesis of this disease.

The role of human herpesvirus-8 in the pathogenesis of multiple myeloma.

Human herpesvirus-8 has been strongly implicated in the pathogenesis of KS, BCBL, and multicentric Castleman's disease. Evidence for its role in the pathogenesis of multiple myeloma is accumulating. Human herpesvirus-8 is detectable in the nonmalignant bone marrow dendritic cells from most myeloma patients. In addition, HHV-8 is also detected in the peripheral blood of most myeloma patients. In contrast, this virus is rarely detected in close contacts of myeloma patients, healthy individuals, or patients with other malignancies. Furthermore, only about one fourth of patients with MGUS are infected with HHV-8. Sequencing of HHV-8 DNA isolated from myeloma patients shows both minor differences among patients and a conserved deletion unique to myeloma compared with HHV-8 in other malignancies. Consistent expression of both the viral homologues of IRF and IL-8R in myeloma suggests a possible role for these transforming viral genes in the pathogenesis of this disease. Although the described association between multiple myeloma and HHV-8 implies a causal role in the pathogenesis of this disease, no cause-and-effect relationship is yet demonstrated. Evidence may be obtained directly by fulfilling Koch's postulate in an animal model and indirectly through therapeutic interventions with antiviral agents or through extensive epidemiological studies. Such epidemiological studies would be greatly facilitated by the development of antibodies directed against the HHV-8 viral proteins uniquely present in myeloma. A direct or indirect causal effect of HHV-8 has potentially enormous implications for the therapeutic benefit of antiviral agents and preventative strategies using vaccines. There is, indeed, preliminary evidence that antiviral therapy in HIV-infected patients reduces the risk or development of KS. Clinical improvement in patients with KS treated with antiviral agents has also been reported. These observations suggest that future treatment strategies to combat multiple myeloma may include antiviral agents.

Effects of chronic nicotine and pilocarpine administration on neocortical neuronal density and [3H]GABA uptake in nucleus basalis lesioned rats.

We investigated the possible long-term neuroprotective roles of (-)nicotine and muscarinic agonist, pilocarpine, in the neocortices of rats receiving bilateral nucleus basalis lesions. Ibotenic acid-lesioned animals eventually displayed a 15-20% reduction in the density of neocortical Nissl staining neurons in layers II, III and VI, as well as a 27% loss in high-affinity GABA uptake 8 months post-lesioning. Deficits were not observed at earlier intervals. (-)Nicotine (0.2 mg/kg, i.p.) or (-)nicotine plus pilocarpine (1 mg/kg, i.p.) attenuated these losses when administered once daily to rats from 5-8 months post-lesioning. Pilocarpine alone had no protective effect on neuronal density or GABA uptake. These results suggest that nicotine receptor activation may counteract neocortical neuronal loss/atrophy following loss of ascending basal forebrain neurons.