FELINE LEUKEMIA REMISSION AND OTHER ARTICLES
- Note from Page Author, Dr. John Raymond Baker,DC
In the 1980s, especially mid to late 1980s, there was
seemingly more research on trying to bring FeLV
into remission, using Staphylococcus Protein A.
The Liu, Good, Trang, et al, study, mentioned first,
is probably one of the more well known of these
studies. As a layperson, what I see in both this study,
and another, is that there is the removal of the
CIC or circulating immune complexes, and the
 immunoglobulin G, from the blood plasma, and, the
result is, clearance of Lymphosarcoma (LSA).
But, more to the point, the second study says this:
"One serological parameter that always correlated
with complete clearance of. FeLV was development
of free antibodies to FeLV-AB gp70."

Farther down this page, you will note that there
are three main strains of FeLV. These are FeLV-a,
FeLV-b, and FeLV-c. The "A" form, apparently is
the original strain, and in many ways, one may see
it as not being as virulent as say, "C". Apparently,
in the infected cat, the FeLV-A, can be altered to
form the FeLV-b and/or FeLV-c. In cats with a
combination of the FeLV-a and FeLV-b, the incidence
of neoplasia (the development of cancerous tumors),
is higher than a cat with the FeLV-a alone. The FeLV-c,
is more associated with development of erythroid
hypoplasia, and therefore, development of severe anemia.

http://www.pnas.org/content/81/20/6471.abstract

Remission of leukemia and loss of feline leukemia virus in cats injected with Staphylococcus protein A: association with increased circulating interferon and complement-dependent cytotoxic antibody

  1. W T Liu, 
  2. R A Good, 
  3. L Q Trang, 
  4. R W Engelman, and 
  5. N K Day

Abstract

We have injected purified Staphylococcus aureus protein A intraperitoneally into leukemic cats infected with feline leukemia virus, into cats persistently infected with feline leukemia virus but without hematologic or cytologic abnormalities, and into healthy cats without feline leukemia virus infection. Pre- and post-treatment serum samples were evaluated sequentially for interferon activity and for complement-dependent cytotoxic antibody. Our results indicate that serum interferon increased dramatically (less than 3 to 324 units/ml) during treatment only in cats that responded to staphylococcal protein A therapy. Increase of interferon preceded or was closely associated with increasing levels of cytotoxic antibody, loss of viremia, and correction of cytological and hematological abnormalities of three leukemic cats. The cytotoxic antibody was shown to be specific for envelope glycoprotein gp70 of the feline leukemia virus. One persistently feline leukemia virus-infected cat without leukemia that became nonviremic also developed high levels of interferon and specific cytotoxic antibody. By contrast, interferon levels of cats not responding to treatment had levels of less than 3 to 27 units/ml. Normal healthy cats injected with staphylococcal protein A showed moderate transient increases of interferon but no detectable cytotoxic antibodies to FL-74 cells. These data suggest that interferon and cytotoxic antibody may play important, possibly complementary roles in inducing remission of leukemia and loss of viremia in cats treated with staphylococcal protein A.

 

  
http://www.ncbi.nlm.nih.gov/pubmed/2543084
Remission of FeLV-associated lymphosarcoma and persistent viral infection after extracorporeal immunoadsorption of plasma using staphylococcal protein A columns: details of immune response.

Snyder HW Jr, Reed DE, Jones FR.

IMRE Corp., Seattle, WA 98109.

Sixteen feline leukemia virus (FeLV)-infected cats with lymphosarcoma (LSA) were treated by extracorporeal immunoadsorption using staphylococcal protein A columns in order to remove immunoglobulin G (IgG) and circulating immune complexes (CIC) from plasma. Complete viral clearance and long-lasting tumor regression were achieved in nine of the cats and tumor regression without virus clearance was observed in two other cats. Since LSA cats rarely go into spontaneous remission, and since other forms of therapy are ineffective, these cats offered a unique system for analyzing details of the immune response to LSA and FeLV as they are cleared. Immunological parameters associated with the FeLV and LSA responses were assessed in detail in three responder cats and three nonresponders during the treatment and follow-up periods. Two serological parameters that always correlated with complete clearance of LSA were development of precipitating antibodies against FeLV-C gp70 and development of cytotoxic antibodies that kill cultured FL74 LSA cells in the presence of complement. The precipitating antibodies were detected prior to the clearance of LSA and prior to the detection of free cytotoxic antibodies. One serological parameter that always correlated with complete clearance of. FeLV was development of free antibodies to FeLV-AB gp70. Quantitative levels of FeLV-specific CIC and feline oncornavirus-associated cell membrane antigen (FOCMA)-specific CIC correlated well with fluctuating levels of the corresponding antigens and antibodies. These results suggest that the staphylococcal protein A treatment columns remove CIC "blocking factors" directly or indirectly and thereby stimulate existing antibody responses. These antibodies mediate clearance of FeLV and LSA.

PMID: 2543084 [PubMed - indexed for MEDLINE

 

 

  

http://www.jimmunol.org/cgi/content/abstract/132/3/1538

Clearance of feline leukemia virus from persistently infected pet cats treated by extracorporeal immunoadsorption is correlated with an enhanced antibody response to FeLV gp 70

HW Snyder Jr, MC Singhal, WD Hardy Jr and FR Jones
Six persistently feline leukemia virus (FeLV)-infected pet cats were treated by extracorporeal immunoadsorption with Staphylococcus aureus Cowan I (SAC) to remove circulating immune complexes and immunoglobulin G (IgG) from plasma. In three of these cats, the FeLV infection was eliminated, whereas in the other three cats the infection persisted. The amounts of peripheral blood leukocyte (PBL)-associated FeLV, soluble FeLV envelope glycoprotein (gp70) antigens in serum, and FeLV- gp70-specific antibodies were determined in all six cats at different times during treatment. In all of the cats, there were fluctuations in the amounts of FeLV-positive PBL and of serum antigen related to FeLV gp70. The one serologic parameter that always correlated with complete clearance of FeLV in the responder cats was the development of free antibodies to gp70. These results suggest that extracorporeal immunoadsorption treatment stimulates an existing low level antibody response to FeLV in some cats, and that these antibodies mediate the clearance of FeLV. The results also suggest that determination of antibody titer to FeLV is of value in predicting the outcome of extracorporeal immunoadsorption treatments as well as when treatment may be terminated.

 

  

http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/57000.htm

Etiology and Epidemiology:
FeLV is a retrovirus in the family Oncovirinae. Other oncoviruses include feline sarcoma virus, mouse leukemia viruses, and 2 human T-lymphotropic viruses. Although oncogenesis is one of their more dramatic effects, oncoviruses cause many other diseases, including degenerative, proliferative, and immunologic disorders.
There are 3 main FeLV subgroups of clinical importance. Subgroup A viruses are found in all naturally infected cats. FeLV-A, the original, archetypical form of the virus, is efficiently transmitted among cats. FeLV-A viruses tend to be less pathogenic than viruses of the other subgroups, but some strains cause severe immunosuppression. Almost all naturally infected cats are originally infected by FeLV-A. Within the infected cat, FeLV-A is sometimes altered to produce FeLV-B and FeLV-C viruses. FeLV-B is found in ~50% of naturally infected cats, along with FeLV-A. FeLV-A and FeLV-B together are more frequently associated with neoplastic diseases than is FeLV-A alone. FeLV-C viruses are isolated from only 1% of naturally infected cats, along with FeLV-A and sometimes both FeLV-A and FeLV-B. The presence of FeLV-C in an infected cat is strongly associated with the development of erythroid hypoplasia and consequent severe anemia. Viruses of all 3 subgroups are detected (but cannot be distinguished) by commonly used FeLV diagnostic test kits.
The incidence of FeLV infection is directly related to the population density of cats. Infection rates are highest in catteries and multicat households, especially when cats have access to the outdoors. In the USA, 1-2% of healthy stray urban cats are persistently viremic. Not surprisingly, much higher percentages of sick, “at risk” cats are found to be infected.
Persistently infected, healthy cats are the major reservoir of FeLV. Carriers excrete large quantities of virus in saliva. Lesser amounts of virus are excreted in tears, urine, and feces. Oronasal contact with infectious saliva or urine is the most likely mode of transmission. Nose-to-nose contact, mutual grooming, and shared litter trays and food dishes facilitate transmission. Bite wounds from infected cats are an efficient mode of transmission but occur relatively infrequently in cats kept indoors 100% of the time. Bites may be a more important mode of transmission in indoor-outdoor cats.
Age resistance is significant. Young kittens are much more susceptible than adults. The virus may be transmitted vertically (in utero or by milk) or horizontally (by secretions and excretions). Because FeLV is a fragile, enveloped virus and because of age resistance, horizontal transmission between adults usually requires prolonged, intimate contact. In addition, the dose required for oronasal transmission of the virus is relatively high.
 
Pathogenesis:
After oronasal inoculation, the virus first replicates in oropharyngeal lymphoid tissue. From there, virus is carried in blood mononuclear cells to spleen, lymph nodes, epithelial cells of the intestine and bladder, salivary glands, and bone marrow. Virus later appears in secretions and excretions of these tissues and in peripheral blood leukocytes and platelets. Viremia is usually evident 2-4 wk after infection. The acute stage of FeLV infection (2-6 wk after infection) is rarely detected. It is typically characterized by mild fever, malaise, lymphadenopathy, and blood cytopenias.
In ~70% of adult cats, viremia and virus shedding are transient, lasting only 1-16 wk. A few cats continue to shed virus in secretions for several weeks to months after they cease to be viremic. Virus may persist in bone marrow for a longer period, but even this latent, or sequestered, infection usually disappears within 6 mo. Some FeLV-exposed cats (~30%) do not mount an adequate immune response and go on to become persistently (ie, permanently) viremic. Persistently viremic cats develop fatal diseases after a variable time period.
 
Disorders Caused by FeLV:
FeLV-related disorders are numerous and include immunosuppression, neoplasia, anemia, immune-mediated diseases, reproductive problems, and enteritis.
The immunosuppression caused by FeLV is similar to that caused by feline immunodeficiency virus ( Viral-induced Immunodeficiencies). There is an increased susceptibility to bacterial, fungal, protozoal, and other viral infections. Numbers of neutrophils and lymphocytes in the peripheral blood of affected cats may be reduced, and those cells that are present may be dysfunctional. Many FeLV-positive cats have low blood concentrations of complement; this contributes to FeLV-associated immunodeficiency and oncogenicity because complement is vital for some forms of antibody-mediated tumor cell lysis. Much of the immunodeficiency caused by FeLV is thought to be due to the high degree of viral antigenemia.
Lymphoid or myeloid tumors (eg, lymphoma, lymphoid leukemia, erythremic myelosis) develop in up to 30% of cats persistently infected with FeLV. Although FeLV-negative (ie, nonviremic) cats also develop these tumors, they may still be induced by FeLV, as many negative cats with lymphoma have viral sequences that can be detected by immunohistochemistry and PCR. Such cats may have been previously infected with FeLV despite negative test results for the virus. The transient presence of FeLV could have triggered lymphoma. However, the persistence of FeLV antigen increases the risk of lymphoma by as much as 60-fold compared with an FeLV-negative cat. Lymphoma is the most frequently diagnosed malignancy of cats. Most American cats with mediastinal, multicentric, or spinal forms of lymphoma are FeLV-positive. However, in some parts of the world, these forms of lymphoma are becoming much less common, and the proportion occurring in FeLV-positive cats is decreasing. This may be related to effective control of FeLV. Renal and GI forms of lymphoma are more likely to be found in FeLV-negative cats.
Leukemia is a neoplastic proliferation of hematopoietic cells originating in the bone marrow. The cell lines that become neoplastic are neutrophils, basophils, eosinophils, monocytes, lymphocytes, megakaryocytes, and erythrocytes. In cats, the leukemias are strongly associated with FeLV infection and sometimes (but not always) associated with neoplastic cells circulating in the blood. Lymphoid leukemias are further divided as acute and chronic. Acute lymphocytic leukemia is characterized by lymphoblasts circulating in the blood. In chronic lymphocytic leukemia, there is an increased number of circulating lymphocytes that have normal morphology.
The anemia caused by FeLV is usually nonregenerative and normochromic. There is frequently an idiosyncratic macrocytosis. About 10% of FeLV-related anemias are hemolytic and regenerative. This form of anemia may be associated with hemobartonellosis or immune-mediated hemolysis, or both.
Immune complexes formed in the presence of moderate antigen excess can cause systemic vasculitis, glomerulonephritis, polyarthritis, and a variety of other immune disorders. In FeLV-infected cats, immune complexes form under conditions of antigen excess, because FeLV antigens are abundant and anti-FeLV IgG antibodies are sparse. These conditions are ideal for the development of immune-mediated disease.
Reproductive problems are common; 68-73% of infertile queens have been reported to be FeLV-positive, and 60% of queens that abort are FeLV-positive (although abortion is a relatively uncommon cause of feline infertility). Fetal death, resorption, and placental involution may occur in the middle trimester of pregnancy, presumably as a result of in utero infection of fetuses by virus transported across the placenta in maternal leukocytes. Occasionally, infected queens give birth to live, viremic kittens. Latently infected (ie, nonviremic) queens may pass virus on to their kittens in milk.
Enteritis, resembling feline panleukopenia both clinically and histopathologically, may develop. Clinical signs include anorexia, depression, vomiting, and diarrhea (which may be bloody). Because of the concurrent immunosuppression associated with FeLV infection, septicemia may develop. Evidence suggests that FeLV and feline panleukopenia virus may act synergistically to produce this syndrome.
Other disorders may also develop. FeLV occasionally causes a neuropathy leading to anisocoria, urinary incontinence, or hindlimb paralysis. Certain FeLV-induced lymphomas can produce identical clinical signs. If antineoplastic therapy is planned, it is important to distinguish neoplasia from neuropathy. FeLV can also cause quasineoplastic disorders such as multiple cartilaginous exostoses (osteochondromatosis).
 
Diagnosis:
Two types of tests are readily available for clinical use. The immunofluorescence assay (IFA) tests for the presence of FeLV structural antigens (eg, p27 or other core antigens) in the cytoplasm of cells suspected to be FeLV-infected. In clinical practice, peripheral blood smears are usually used for the IFA, but cytologic preparations of bone marrow or other tissues can also be used. The IFA is considered to be the most reliable but requires submission to a commercial laboratory, so results are delayed. IFA-positive cats are considered to be persistently viremic and have a poor longterm prognosis.
The more convenient ELISA can be performed in the veterinary clinic and tests for the presence of soluble FeLV p27. FeLV antigen may be present in the absence of intact, infectious viral particles because excess FeLV antigens are released from infected cells free of viral particles. The ELISA detects antigenemia rather than viremia. Several different test kits are available; most have sensitivities and specificities of 98%. Accuracy can be improved by running both the IFA and ELISA on the same cat.
Diagnosis of FeLV-induced neoplasia is similar to that of other tumors. Cytologic examination of fine-needle aspirates of masses, lymph nodes, body cavity fluids (eg, pleural effusion), and affected organs may reveal malignant lymphocytes. Bone marrow examination may reveal leukemic involvement, even when the peripheral blood appears normal. Biopsy and histopathologic examination of abnormal tissues is often necessary for diagnostic confirmation.
 
Treatment:
Ideally, an FeLV-infected cat would be identified early and treated to eradicate the retroviral infection before FeLV-related diseases had time to develop. Unfortunately, eradication of retroviral infections at any stage of disease is extremely difficult. Most infected cats are persistently viremic by the time infection is diagnosed.
Many treatments have been administered in an attempt to reverse viremia or decrease clinical signs associated with FeLV infection. Anecdotal reports of antiviral agents and immunotherapeutic agents reversing viremia, improving clinical signs, and prolonging survival are abundant. Controlled studies using naturally infected cats have been unable to substantiate a benefit from these therapies.
FeLV-positive cats can live without major diseases for several years. Stress and sources of secondary infection should be avoided. The cat should remain indoors 100% of the time to reduce the risk of exposure to infectious agents and to prevent transmission of the virus to other cats. Routine prophylactic care for FeLV-infected cats is more important than for uninfected cats. Routine vaccinations should be administered based on the risk to the cat, with rabies vaccinations given to comply with local laws. FeLV vaccinations should not be administered, as there is no evidence to suggest a benefit. Physical examinations focusing on external parasites, skin infections, dental disease, lymph node size, and body weight should be performed every 6 mo. Administration of an anthelmintic at these visits is recommended. All infected cats should be neutered. Owners should be advised to watch for signs of FeLV-related disease, particularly secondary infections. Therapy for such infections or other illnesses should be more aggressive and of longer duration, as the immunocompromised condition renders the cat less able to fight diseases naturally.

Lymphoma Treatment:

Feline lymphoma can be treated with cytotoxic drugs. These drugs may cause significant toxicities if not dosed and administered properly. (See alsoantineoplastic agents, Antineoplastic Agents: Introduction .) Most cytotoxic drugs are also carcinogens and must be handled properly. Before undertaking treatment with these drugs, veterinarians should familiarize themselves with proper dosing and administration, appropriate monitoring of the patient, toxicities and complications, and safe handling to prevent exposure of veterinary personnel and owners to the agents and their metabolites. Treated properly, most cats do not experience significant toxicities and enjoy a good quality of life.
About 50% of cats with lymphoma that are treated will obtain a complete remission (ie, no clinical evidence of disease). FeLV-negative cats that attain a complete remission live an average of 9 mo, and FeLV-positive cats have an average survival of 6 mo. Cats not treated or those not responding to treatment survive ~6 wk.
Many protocols for treatment of feline lymphoma have been published; most use similar drugs with differing schedules of administration. One widely used protocol consists of an intensive induction phase (vincristine 0.75 mg/m2, IV, weekly for 4 wk, cyclophosphamide 300 mg/m2, PO every 3 wk on the same day as vincristine, and prednisone 10 mg/cat, PO, sid throughout the protocol), followed by a less intensive maintenance phase (vincristine and cyclophosphamide given every 3 wk on the same day, prednisone continued daily). Treatment is continued for 1 yr or until relapse. With this protocol, 79% of cats attained remission and average survival was 150 days. Changing the maintenance protocol to doxorubicin 25 mg/m2, IV, every 3 wk, provided an average remission of 281 days. When relapse occurs, the drug regimen can be changed and a second remission achieved; however, second remissions seldom last as long as the first.
Acute lymphocytic leukemia is treated with the same protocol as lymphoma, but only ~25% of cats obtain remission. For those that obtain remission, the average length is 7 mo. Chronic lymphocytic leukemia is best treated with chlorambucil (2 mg/cat, PO) and prednisone (40 mg/m2, PO), given every other day on alternating days. Leukemias other than lymphocytic are rarely treated because the cats are extremely ill and very few respond to therapy.
 
Prevention and Control:
Testing should be mandatory in the following situations: 1) all kittens at their first veterinary visit, so the owners can be counseled regarding a cat that tests positive (as is routinely done for congenital abnormalities), 2) all cats prior to entering a household with existing uninfected cats, 3) all cats in an existing household prior to admission of a new, uninfected cat, and 4) all cats prior to their first FeLV vaccination.
FeLV vaccines are intended to protect cats against FeLV infection or, at least, to prevent persistent viremia. Types of vaccines include killed whole virus, subunit, and genetically engineered. Vaccines may vary in protective effect, and manufacturers’ claims and independent comparative studies should be carefully noted. Vaccines are indicated only for uninfected cats; there is no benefit in vaccinating an FeLV-positive cat. The cat’s risk, of exposure to FeLV-positive cats should be assessed, and vaccines used only for those cats at risk. Although the risk of tumor development is low, FeLV vaccines have been associated with the development of sarcomas at the vaccination site. Uninfected cats in a household with infected cats should be vaccinated; however, other means of protecting uninfected cats (eg, physical separation) should also be used. Constant exposure to FeLV-infected cats is likely to result in viral transmission regardless of vaccination status.
 
Zoonotic Risk:
Some strains of FeLV can be grown in human tissue cultures. This has led to concerns of possible transmission to humans. Several studies have addressed this concern; none have shown any evidence that any zoonotic risk exists.

 

  

 

http://www.jleukbio.org/cgi/content/abstract/61/6/654

Journal of Leukocyte Biology, Vol 61, Issue 6 654-666, Copyright © 1997 by Society for Leukocyte Biology

JOURNAL ARTICLE

Immunosuppressive retroviral peptides: immunopathological implications for immunosuppressive influences of retroviral infections

S Haraguchi, RA Good, GJ Cianciolo, RW Engelman and NK Day 
 Department of Pediatrics, All Children's Hospital, University of South Florida College of Medicine, St. Petersburg 33701, USA.

Studies of the effects of retroviruses on the immune system, which date back through thirty years of investigations, are reviewed. In the earliest published studies in the 1960s, it was demonstrated that mice infected with oncogenic viruses were immunosuppressed. Since then, numerous articles have been published describing profound immunodeficiencies observed in vivo in humans infected with human immunodeficiency virus and in animals such as cats infected with the feline immunodeficiency virus. In vitro investigations have shown that inactivated retroviruses or transmembrane envelope protein p15E as well as a synthetic 17-amino acid peptide (CKS-17) impressively conserved within the transmembrane envelope protein of several animal or human retroviruses are highly immunosuppressive. More recently, dysfunction of cytokines produced by CKS-17 at both a cellular and molecular level have been found to mimic influences observed in vivo in patients infected with the human immunodeficiency virus. CKS-17 has also been shown to induce cAMP in vitro. The significance of these observations to understanding the immunological disturbances observed in malignancy, cytokine biosynthesis, and modulations of immune functions through cAMP is discussed. 

 

  

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/70/6/1880

Experimental transmission and pathogenesis of immunodeficiency syndrome in cats

EA Hoover, JI Mullins, SL Quackenbush and PW Gasper

Department of Pathology, Colorado State University, Fort Collins 80523.

We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acuteimmunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely symptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal cryptepithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.

Volume 70, Issue 6, pp. 1880-1892, 12/01/1987
Copyright © 1987 by The American Society of Hematology