From: bigoldberg@igc.apc.org (Billi Goldberg)
Newsgroups: sci.med.aids
Subject: KS and Immunosuppression
Date: 26 Sep 92 17:51:30 GMT
Organization: unspecified
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6229

The following excerpts are from Kaposi's Sarcoma: A Text and Atlas, 
edited by Geoffrey J. Gottlieb, M.D. and A. Bernard Ackerman, M.D.  The 
text was published in 1988 by Lea & Febiger, Philadelphia.
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CHAPTER 15, IMMUNOSUPPRESSIVE THERAPY BY DARRYL M. BRONSON, M.D., M.P.H.

Page 241:"The occurrence of Kaposi's sarcoma in patients receiving 
immunosuppressive therapy has been well documented. The close temporal 
relationship between the institution of immunosuppressive therapy and 
the onset of Kaposi's sarcoma, and the regression of the disease in some 
patients after the cessation or reduction of immunosuppressive therapy, 
strongly suggest a causal relationship."

Page 243:"At least 49 cases of Kaposi's sarcoma occurring in patient's 
receiving immunosuppressive therapy has been reported. Twenty-two of 
these cases involved recipients of rental transplants. One patient 
developed Kaposi's sarcoma following cardiac transplantation. The rest 
of the patients received corticosteroids and/or cytotoxic drugs for 
treatment of a wide variety of benign and malignant diseases. The causal 
relationship between Kaposi's sarcoma and immunosuppressive therapy in 
many of the patients in this latter group is not nearly as strong as it 
is in the recipients of transplants.

Page 246-247:"Most patients receive either corticosteroid therapy alone 
or in combination with azathioprine for immunosuppression. All of the 
recipients of transplants in whom the type of therapy is recorded 
received the combination of a corticosteroid and azathioprine. In 
contrast, only 5 of 26 patients who received immunosuppressive therapy 
for the treatment of other diseases were given the combination of a 
corticosteroid and azathioprine. Cyclophosphamide, melphalan, and 
antilymphocyte serum were also used in the treatment of several 
patients.

"The lesions of Kaposi's sarcoma appear in three months to five years 
after the start of immunosuppressive therapy in the recipients of 
transplants and from one month to ten years after the start of therapy 
in the patients treated for other conditions. In the recipients of 
transplants, the mean duration of treatment before the Kaposi's sarcoma 
appeared was 15 months, and in those patients treated for other 
conditions, the average interval was 34 months.

"The duration of immunosuppressive therapy before the development of 
Kaposi's sarcoma is considerably shorter in those patients receiving a 
corticosteroid and azathioprine (mean, 15 months) than in those patients 
receiving a corticosteroid alone or a corticosteroid in combination with 
an immunosuppressive agent other than azathioprine (mean, 44 months). 
This suggests a synergistic effect of azathioprine and corticosteroids 
in the development of Kaposi's sarcoma, but it may also reflect a 
fortuitous occurrence of Kaposi's sarcoma in many of the patients 
treated with a corticosteroid alone.

"The coincidence of Kaposi's sarcoma with a second primary neoplasm, 
especially of the lymphoreticular system, has been noted by many 
authors. Kaposi's sarcoma most commonly appears at the same time or 
after the other neoplasm. Consequently, the role of immunosuppressive 
therapy, in particular of corticosteroids, cyclophosphamide, and 
melphalan, in the development of Kaposi's sarcoma in patients with 
lymphoreticular malignancies may be questioned."

ETIOLOGY (Page 248-250):"It appears that several factors are operative 
in the pathogenesis of Kaposi's sarcoma. These factors include genetic 
predisposition, infectious agents, in particular viral infections, and 
disturbances of the immune system.

"A high incidence of infection with cytomegalovirus in recipients of 
rental transplants and in homosexual men with or without Kaposi's 
sarcoma has been shown. Moreover, elevated antibody titer to 
cytomegalovirus have been found in patients with classic Kaposi's 
sarcoma, and sequences of DNA from cytomegalovirus have been detected 
with neoplastic cells from biopsy specimens. Although these studies 
suggest a close association between cytomegalovirus and Kaposi's 
sarcoma, they do not establish cytomegalovirus as a causative agent of 
the disease, because infection with cytomegalovirus may result from 
immunosuppression. Furthermore, some investigators have not been able to 
detect cytomegalovirus antigens in biopsy specimens of Kaposi's sarcoma.

"Abnormal immune function, principally of cell-mediated immunity, has 
been described in some patients with Kaposi's sarcoma. An inability to 
sensitize Africa patients who have widespread Kaposi's sarcoma to 
dinitrochlorobenzene was shown by Masters et al. However, normal delayed 
hypersensitivity was found in patients with localized nodular lesions. 
Similarly, Taylor et al. demonstrated a diminished lymphocyte response 
in vitro to phytohemagglutinin and autologous stimulation of neoplastic 
cells in African patients who had widespread Kaposi's sarcoma compared 
to those who had more localized disease.

"The cellular immune function in vitro of 3 patients who had Kaposi's 
sarcoma and who had renal transplants was studied by Harwood et al. and 
was found to be subnormal in each patient. In one of the patients the 
cellular immune responses returned to normal when the Kaposi's sarcoma 
was in almost complete remission. The administration of azathioprine had 
been stopped, but prednisone has been continued. In another patients, 
the response improved, but were still subnormal following radiotherapy 
and partial remission of the Kaposi's sarcoma. Azathioprine had been 
discontinued one month prior to the initial tests, but prednisone had 
been continued. The third patient was tested only following 
radiotherapy, when his Kaposi's sarcoma was in complete remission. The 
cellular immune response was abnormally low, but not as low as the 
pretreatment responses of the other two patients. The patient continued 
to receive azathioprine and prednisone. Skin reactivity to 
dinitrochlorobenzene was tested in the first 2 patients prior to 
treatment of their sarcomas and was negative. Unfortunately, there was 
no control group of patients with renal transplants but without Kaposi's 
sarcoma with which to compare the results..

"Several theories have been advanced to explain the role of 
immunosuppressive therapy in the development of Kaposi's sarcoma. First, 
impaired immune defenses caused by immunosuppressive therapy may make 
patients more susceptible to viral infections and permit potentially 
oncogenic viruses to proliferate. Second, suppression of mechanisms of 
immunologic surveillance by immunosuppressive therapy may allow 
undetected malignant clones of cells to emerge. Still another theory 
suggest that Kaposi's sarcoma develops as a result of chronic antigenic 
stimulation, such as occurs following transplantation of organs or in 
autoimmune diseases. Feedback mechanisms that ordinarily regulate the 
immune response are inhibited in patients treated with immunosuppressive 
therapy. In the course of this reaction, an angiogenesis factor is 
produced, which promotes proliferation of mesenchymal and endothelial 
cells. An oncogenic virus is either transferred to or induced in the 
cells that are responding to the angiogenesis factor and leads to 
neoplastic transformation of these cells.

"It is also possible that immunosuppressive medication may have a direct 
carcinogenic effect. However, the short interval between the initiation 
of immunosuppressive therapy and the onset of Kaposi's sarcoma makes 
this unlikely. Induction periods for the most chemical carcinogens in 
humans are at least several years, if not decades."
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