Natural killer (NK) cells were identified by their ability to kill target cells without previous sensitization. Similar to the Krull Glaive from the movie if the same name. Her paresis of the right arm gradually improved without any medication during her hospital course. And continue we did, until five a.m. In cell hybrids between nonpermissive Don/a23 cells and human fibroblasts containing a t(11;15) (p11;p12) translocation, HSV-1 production was dependent solely on the presence of either human chromosome 11 or the der(11) (p11→qter) translocation product containing the long arm of chromosome 11. When, on May 5, she was hospitalized for the first time for treatment of the vaccinia necrosum, the ulcer measured 5×5 cm and yielded vaccinia virus on culture. Furthermore, NK cells armed by latent infection protected the host against a lethal lymphoma challenge.
Initial work-up revealed a hemoglobin of 10.8, white blood cell count of 3,200/mm((3)), and normal immunoelectrophoresis, but specific immunoglobulins were low (IgA = 10 mg/100 ml, IgG = 310, and IgM = 15). Intermediate PPD, histoplasmin, candida, and mumps skin tests were negative. For the next few days I obsessed over my strange mosquito bite and its slow growth and rapid change when it dawned on me, I’d misdiagnosed myself. The perineal ulcers cleared almost entirely and became negative on virus culture. However, the left arm ulcer was unchanged and continued to yield vaccinia virus. Resting NK cells from specific pathogen-free (SPF) laboratory mice illustrate this concept: they express abundant perforin and granzyme (Gzm) B mRNA but minimal perforin and GzmB proteins and are ineffective killers directly ex vivo.12 Efficient cytotoxicity by these cells requires arming (also termed “priming”) to induce the translation of perforin and GzmB mRNA into protein.12 Here, arming refers to an enhanced NK-cell functional capacity in general, as opposed to a specific theory of NK-cell education.11 The arming of murine NK cells for potent cytotoxicity can be induced in vitro by cytokines (eg, interleukin-2 [IL-2] or IL-15), or by activated accessory cells that stimulate NK cells in response to acute infection,12–14 but the mechanisms whereby these arming events occur in the healthy host are unclear. When the patient was rehospitalized from June 1 to June 14, the arm ulcer measured approximately 8×7 cm, but she had no evidence of active genital herpes.
During the second hospitalization, she received VIG, oral thiosemicarbazone, and interferon–5 million units intramuscularly daily for 10 days. When she was discharged on June 14, her arm ulcer was approximately the same size as on admission, and a small lesion, believed to be a minor scratch or mosquito bite, was present on the left thigh. The patient was treated as an outpatient with intravenous interferon, 8 million units, three times a week. The left arm ulcer remained approximately the same size but showed some signs of epithelialization. This hypothesis was formed on the basis of the previous observation that latent herpesviruses have multiple stimulatory effects on the host immune system.18,19 We tested this idea using Murid herpesvirus 4 (MuHV-4, also known as murine gammaherpesvirus-68), a natural pathogen in wild mice20 that is closely related to the human viruses Kaposi sarcoma–associated herpesvirus and Epstein-Barr virus. Both the left arm and the left thigh ulcers repeatedly yielded vaccinia virus. The patient was hospitalized for the third time from July 15 to July 20 for surgical removal of the ulcer on her left thigh and retreatment with interferon, thiosemicarbazone, and VIG.
In addition, she received four doses of transfer factor at the University of Michigan–Ann Arbor. On last examination, the site of the leg lesion was still positive for vaccinia virus, and the arm lesion has shown no signs of improvement. Other modes of therapy being considered include surgical removal of the left-arm ulcer and treatment with thymosin. Viable cell numbers and percentages of NK1.1+CD3− lymphocytes were determined on pooled samples from 2 to 5 mice by the use of trypan blue exclusion and flow cytometry. Editorial Note: To date, the patient has required three hospitalizations for treatment of smallpox vaccination complications for which none of the usual treatments has been effective. The severe course of her herpes and vaccinia infections suggest underlying immunosuppression or deficiency, but no specific immunologic defect has been identified. This case of vaccinia necrosum demonstrates the risk of using smallpox vaccination, a treatment with no proven effectiveness, for herpes disease (1).
The Food and Drug Administration recently published a warning to all physicians on the inappropriate use of smallpox vaccination for herpes infection (2). Disclaimer All MMWR HTML documents published before January 1993 are electronic conversions from ASCII text into HTML. In contrast, we detected no difference in the expression of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand, proteins involved in alternative NK-cell cytotoxicity pathways (supplemental Figure 2). Users should not rely on this HTML document, but are referred to the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.