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Biomedical subjects

B M Wimer

Publications and source records attributed to B M Wimer.

At least 19 recordsLinked to original sources
PubMed2000

Apparent pokeweed mitogen cure of metastatic gum melanoma in an older dog.

Immunotherapy with plant mitogens has been of increasing interest to both authors, although their mutual attraction to these substances over the past two decades occurred independently and has taken divergent pathways from the start. Because of their clinical unavailability, Wimer's efforts have been confined to writing theoretical concepts on potential applications of the mitogens focusing on the L4 isolectin of PHA. Alternatively, Mann has worked actively with laboratory and experimental research involving PWM that he has extracted himself. As a sequel to a pilot study of PWM cancer treatment in pets whereby he supplies the mitogen, protocol, and data sheets and veterinarians supervise the administration, Mann acquiesced to widespread requests for inclusion in an extended investigation. Unfortunately, this arrangement has left Mann with little control over data submission, and until recently, only verbal reports have been received. The recent documentation of a three-year remission and apparent cure of gum melanoma metastatic to regional and hilar lymph nodes and to the lungs in an aged dog following PWM therapy has prompted this case report. The incredible response has inspired more aggressive attempts to obtain information from other recipients of the mitogen. The small total dose of 300 micrograms inducing a remission does speak for the remarkable potency of PWM that may be 500 or more times that of PHA. However, the possibility that melanoma is a uniquely responsive tumor is suggested by a 1971 article indicating complete remission of metastatic melanoma in an 18-year-old lad to an unexpectedly low total dose of 50 mg PHA. Preliminary reports on other tumors treated with PWM indicate some impressive responses have occurred, although they also suggest that Mann's regimen may sometimes require adjustments in dosages and other variables previously reviewed in theoretical PHA-L4 models, to which this case report now contributes validity.

Adjuvants, Immunologic↗
PubMed2000

Mitogen immunotherapy for HIV infections exemplified by phytohemagglutinin and pokeweed mitogen.

The ideal treatment for HIV infections would supplement highly active antiretroviral therapy (HAART) started at the time of initial diagnosis with an agent that can facilitate cure in the briefest time possible to avoid adverse effects of extended HAART such as drug toxicity, noncompliance, and shortened telomere-induced replicative senescence of CD8 cells. As a crucial part of the regimen, the agent must be able to initiate killer reactions against the HIV, replenish CD4 cells, rejuvenate CD8 cells, block HIV invasion of CD4 cells, activate latent HIV-sequestering host cells, stimulate effective immune reactions against malignancies, generate effective immune responses against conventional and opportunistic infections, circumvent the treatment- and immune response-evading capacities of HIV mutations, and reconstitute immune and hematopoietic competences. Over the past decade, the L4 isolectin of PHA has been presented as a mitogen capable of meeting these goals as they have become defined, but its potential has not been recognized sufficiently to expedite its evaluation. Pokeweed mitogen (PWM) offers the major advantage of being up to 500 times more potent than PHA and has much smaller molecular weight (22,500 to 38,000 daltons versus approximately 125,000 daltons). Given by injection, it has demonstrated curative effects for metastatic malignancies in dogs and cats unassisted by ancillary therapy. Unlike PHA, PWM does not block the attachment of HIV gp 120 to CD4 membrane receptors, but it can obstruct CD4 cell invasion by binding with the CD4 receptors themselves. An expeditious manner of applying PWM would be to give minute doses of an ultra potent root extract capable of inducing a benign plasmacytoid lymphoblastic leukemoid reaction that reverses spontaneously after about 10 weeks. This might prove curative given in conjunction with HAART or possibly even without it. The preferred route of administration for the mitogens in humans would be intravenous although oral administration might prove more advantageous, particularly with PWM. These mitogens might be used singly or, if necessary, in combination after the toxicities have been carefully delineated in humans. Economic forces might restrict treatment availability solely to orally administered PWM therapy in poverty-stricken undeveloped countries if this were shown to be curative. These proposals originating from the authors long concerned with mitogen management of various disorders including HIV infections but only peripherally involved with their clinical applications, are offered for consideration by investigators perceptive enough to see the wisdom of exploring the curative possibilities.

Adjuvants, Immunologic↗
PubMed1998

PHA for aplastic anemias: the alpha but not the omega of mitogen therapies.

This manuscript updates an analysis of the foremost clinical investigation of PHA for aplastic anemias and other disorders associated with impaired hematopoiesis during the years 1963-1967. Humble displayed remarkable insight in motivating the trials long before the recent era during which these disorders have become much better understood. That investigation actually consisted of a series of small pilot studies totaling only 44 patients involving all categories in the aplastic group and 15 miscellaneous disorders mostly neoplastic or premalignant. The most serious of several faults with the studies was the inadequacy of dosages applied, yet much better results were observed than might have been anticipated. Mitogens such as the L4 isolectin of PHA might be applied to treat aplastic anemias in three different ways. (1) For milder direct cytotoxicity types, a stimulating regimen should be applied to increase the production of growth factors and thereby hasten recovery from aplasia. (2) Where hematopoietic stem cell allo-engraftment is needed to replace severely damaged marrow, the mitogen should be included in the preparative regimen. (3) The suppressive protocol of a mitogen that maintains total T cell activation should be added to an established drug regimen such as cyclosporin and antilymphocyte globulin in treating the immuno-mediated aplastic anemias not only to provide superior suppression but to help prevent the late emergence of clonal disorders. The models of L4 isolectin application present advantages not fully offered by any of the other immuno-therapies currently available: broad scope of activities, low morbidity, ease of administration, favorable cost-effectiveness, assurance of reconstituted immune competence, and high potential for cure. However, a more potent mitogen than PHA-L4 not inhibited by serum glycoproteins or immunoglobulins and exhibiting a broader range of modulation would be preferred. A publication by Mann et al. in 1991 suggested that pokeweed mitogen (PWM) showing hundreds of times the potency of PHA-L4 would meet these criteria. Abbreviated reports on two of the studies in the report indicated that PWM had induced lasting remissions of cancers in dogs with nine injections in the mid-range of microgram doses over three weeks. The key study done by Mann himself demonstrated complete disappearance of canine gliomas in a carefully devised humane model applied to five dogs in which the transplantable tumor was established by extradural injection. Also impressive were lasting remissions of autonomous solid neoplasms in four dogs under the care of local veterinarians given PWM supplied by Mann. The critical aspect of these studies, both of which have been extended substantially, is the need keep the dosage within a precisely determined range to avoid loss of efficacy and possibly the occurrence of adverse effects. A review of basic studies now indicates the principle mechanism of response to be binding of PWM with tumor cells that then attract mast cells generated by stem cell factor the production of which is stimulated by the mitogen. Degranulation of mast cell granules releases TNF-alpha and IL-1 at the tumor site with resulting disappearance of neoplastic tissue in the absence of severe systemic effects. For cancer therapy, this represents a highly effective deviation from the stimulation of multiple pathways of immune response usually surmised with mitogens such as PHA-L4. This interpretation illustrates the probability that alternative plant mitogens, each with its unique properties, will likely become available to complement PHA-L4 or displace it from the prime standing as an immunomodulator.

Anemia, Aplastic↗
PubMed1998

Implications of the analogy between recombinant cytokine toxicities and manifestations of hantavirus infections.

The etiologic hantavirus of the 1993 emergence of an acute pulmonary failure syndrome in the area around northwestern New Mexico was quickly recognized as related to the Hantaan virus responsible for the outbreak of Korean epidemic hemorrhagic fever (EHF) among UN troops in 1951. Discovery of the new disease which was named the hantavirus pulmonary syndrome (HPS) and its causative agent the Sine Nombre virus (SNV) inspired detailed comparisons between the two disorders. Major damage to the epithelial cells of the capillaries and arterioles throughout the body leading to extensive capillary leak and subsequent hypotension and shock was the common denominator. The lung capillaries and arterioles were the focus of attack that could lead to rapid pulmonary failure in HPS and the corresponding renal and retroperitoneal vessels that caused a more protracted illness in EHF, but both displayed remarkably similar peripheral blood abnormalities including abnormal mononuclear cells, immature neutrophilia, thrombocytopenia, and hemoconcentration characteristic enough to make blood smear examination a useful tool in early diagnosis. There are evidences that a heavy virus presence in the involved endothelial cells is accompanied by various mononuclear cells capable of generating potent immune response in these areas. Relevant toxic effects of systemically-administered high-dose interleukin-2 for resistant cancers include fever, chills, diarrhea, renal dysfunction, capillary leak syndrome accompanied by hypotension requiring aggressive pressor support, and occasional pleural effusions with diffuse pulmonary infiltrates and hypoxia severe enough to require ventilatory assistance. Peripheral blood mononuclear cells cultured in vitro with IL-2 secrete secondary cytokines such as IL-1, TNF-alpha, and interferon-gamma (IFN-gamma). TNF-alpha, implicated in the pathophysiology of septic shock, is capable of inducing adult respiratory distress syndrome (ARDS) in experimental animals and humans. The strong similarity of these effects to the manifestations noted in the hantavirus diseases justifies the conviction that these and other cytokines involved in potent immune responses would constitute the pathogenic toxic substances predicted by perceptive early investigators of EHF. This concept is favored by clear indications that in both diseases active virus infection disappears the first few days and the ages of involvement correlate with periods of immunocompetence. The paradox of systemic injections of IL-2 that risk hantavirus-type toxicities for treating renal cell carcinoma and melanoma might be avoided by giving potentially more efficacious plant mitogens like PHA as previously reported. The expanded disclosure of a collaborator's method suggesting superior potential for cancer cure involves a unique application of pokeweed mitogen that delivers various cellular and cytokine responses directly to the tumor.

Adult↗
PubMed1998

Immunosuppressive applications of PHA and other plant mitogens.

Phytohemagglutinin was prominent in the evaluation of the immunosuppressive effects of mitogenic lectins that started in 1965 and continued for two decades. Basic studies elucidated the inhibitory actions of PHA on humoral and cellular immune responses in mice, rats, and guinea pigs. Some suppressive effects of this and other mitogens including lentil lectin and Con A were demonstrated on renal, skin, pancreas, and heart allograft rejections in mice, rats, and dogs. In addition to their inherent suppressive activities, these substances have been shown to potently augment the suppression generated by conventional agents. More relevant to tolerance-inducing modulations, the Rigas group showed that in vitro incubation of the parental spleen cells with PHA in the F1 hybrid model before giving them to the F1 mouse virtually abolished the GvH responses. Their explanation was that the donor cells were rendered unresponsive by their reversion to an immature state in which they lost the essential surface receptors. Similar spleen cell suppression was generated by systemic administration of PHA to the parental donor prior to their administration. A method is proposed here for establishing tolerance to either newly introduced or firmly established antigens applying the L4 isolectin of PHA to make non-reactive all T lymphocytes that remain functional in conjunction with full suppression by conventional agents. During the vulnerable period of drug-induced suppression, the host would be protected from infection and bleeding by full nonspecific proliferative activation of the lymphoid and myeloid systems. The establishment of allograft tolerance by preemptive inhibition of responses to newly introduced transplant antigens would be easier to achieve than the reversal of firmly established responses to antigens involved in GvH reactions and autoimmune diseases. The studies of von Boehmer and Kisielow in a transgenic mouse model confirmed that clonal deletion does occur in the thymus whereby corresponding specific thymocytes are destroyed when they encounter self-antigens. Their work suggested that tolerance to self-antigens might be established if immune responses against putative antigen peptides were blocked sufficiently that they would be released to reach the central or peripheral residence sites of their immunologically reactive clones for deletion to occur. This approach to suppressive therapy would be useful for managing the problems of allograft rejection, GvH reactions, and autoimmune disorders even if they fell short of generating complete tolerance. Suppressive treatment with mitogens would also be indicated for the immune-related group of aplastic anemias, but a discussion of these disorders will be deferred to a separate article because of certain aberrations they present.

Animals↗
PubMed1997

Therapeutic immunostimulating effects of plant mitogens exemplified by the L4 isolectin of PHA.

A sizable body of evidence has accumulated showing that the characteristics of certain plant mitogens should endow them with valuable immunomodulating effects. Immune stimulation would be the fundamental function operating through the broad consequences of nonspecific T cell activation following binding with their CD3 or CD2 molecules. Based on in vitro evidences that PHA, operating through the LDCC pathway, might kill any tumor target if it remains present in adequate concentration, the administration of mitogens for cancer therapy would be rational, and the same mechanism should also justify these agents for treatment of certain infections. Being nonerythroagglutinating, although leukoagglutinating in higher concentrations, PHA-L4 serves as a suitable model for immunostimulating activities of the mitogens that can be applied directly or as in vitro activators of adoptive leukocytes. The PHA skin test can be utilized to gauge the serum levels of inhibitory glycoproteins that become elevated in a number of the disorders treatable by the mitogen, thus facilitating necessary dosage modifications. While PHA is the only mitogenic lectin that has been tested clinically, Con A and PWM are the two most widely studied among the alternatives, with others also available and many undoubtedly awaiting discovery. The development of practical methods for producing industrial quantities of nonagglutinating mitogens in pure form should be the goal, and accomplishing the latter might also answer certain hypersensitivity concerns.

Adjuvants, Immunologic↗
PubMed1997

Theoretical benefits of mitogen applications for HIV-1 infections.

Ideal treatment of HIV-1 infections should include an agent that can reverse the capacity of the virus to evade destruction by hiding in sanctuaries and by frequently mutating the epitopes it displays. The rapid proliferation of virions during the years of symptomatic quiescence obligates rapid replacement of CD4+ lymphocytes that leads to a gradual attrition of the T lymphocytes needed to control infections. In vitro evidences suggest that, given systematically, certain mitogenic lectins would interfere with HIV-1 invasion of CD4+ cells by blocking gp120 molecules on the viral membrane before activating T lymphocytes subsequent to binding with their Ti/CD3 molecules. The nonspecific nature of antiviral effector cells generated by this activation should circumvent HIV-1 mutations at the same time it reconstitutes depleted T lymphocytes, stimulates myelopoiesis, and reinforces resistance to malignancies and infections prevalent with the immunodeficiency state. Properly coordinating these effects with appropriate combinations of reverse transcriptase and protease inhibitors could theoretically expedite complete elimination of HIV in a timely fashion that shorten the required treatment duration and excludes the detrimental effects of virus mutations. The proper sequence of this treatment should be maximum reduction of the HIV-1 load with drug combinations, control of complicating infection by other means to reduce mitogen-induced tissue necrosis, and addition of systemic PHA-L4 administration regulated to maintain a 5-10 micrograms/mL serum concentration. The antiviral regimen should be continued an undetermined time beyond when HIV-1 is no longer detectable, and systemic L4 administration until satisfactory immunologic and hematologic competences are re-established. Partially-matched mitogen-activated adoptive leukocyte therapy might be additionally helpful.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Putative effects of mitogenic lectin therapy corroborated by alloactivation data.

A firm theoretical case for PHA and other plant mitogens as superior immunomodulators has previously been presented, but direct confirmatory evidences have been compromised by experimental studies involving excessive dosages of erythroagglutinating PHA that often compromised the circulation in smaller animals, while inadequate amounts were applied in humans because this mitogen's availability in nonagglutinating form was restricted. The resulting underestimation of efficacy has failed to inspire the production of industrial quantities of mitogens required for reliable clinical trials. As a means of circumventing this dilemma, past favorable results from the immuno-stimulating activities of allocativation have been extrapolated to forecast the effects to be anticipated from mitogenic modulation. Such an extrapolation would underrate the latter's impact, which would neither be confined to stimulation nor dependent on the uncertainties of engraftment. This review cites clear examples showing that all recognized immune system pathways have been stimulated by alloactivation except perhaps the ADCC, and an example of this pathway's activation has been shown to have occurred with PHA therapy itself. Of the mitogenic lectins currently available, PHA, Con A, and PWM have each shown rare instances of hypersensitization that hopefully might be eliminated by exclusion of contaminants with recombinant DNA methods of production.

Graft vs Host Disease↗
PubMed1995

Haplotype donor-generated graft-versus-leukemia responses: serendipity revisited.

This re-evaluation of a pilot study conducted nearly three decades ago (1965-1970), in which serendipity played a central role in favorable responses of hematologic malignancies to the administration of adoptive lymphocytes from both parents, has been motivated by clearer understanding. Temporary remissions marking LAK cell-driven graft-versus-leukemia (GvL) responses were observed in four of seven acute leukemia patients associated with unique self-limited graft-versus-host (GvH) reactions that were NK cell and cytokine related. Retinopathy not previously reported in a GvH setting was a consistent manifestation in these patients. Cure was achieved in an eighth patient with acute lymphoblastic leukemia after she had been given effective chemotherapy, an active role for the adoptive therapy indicated by the occurrence of a week of fever suggesting an abortive GvH reaction. Two of five patients with Hodgkin's disease also experienced favorable responses to parental leukocyte therapy, one exhibiting GvH manifestations almost identical to those seen in the acute leukemia patients when given the adoptive therapy successfully to spur recovery from severe herpes zoster that had interrupted curative radiation therapy. The GvH in the other patient was a more typical one, the key effect being an increase in circulating lymphocytes that may have contributed indirectly to cure with subsequent therapy. These and other attempts to apply GvL responses therapeutically, including those currently in favor, exemplify the shortcomings of partial mitogenic responses to alloactivation, which are dependent on engraftment, limited in scope, excessively toxic, and difficult to control. Treatment with mitogens such as PHA would be a superior alternative because of the abilities of these agents to regulate immune responses by simple modulations of dosage, scheduling, and modes of application.

Acute Disease↗
PubMed1990

Characteristics of PHA-L4, the mitogenic isolectin of phytohemagglutinin, as an ideal biologic response modifier.

Phytohemagglutinin retains the properties of a theoretically ideal biologic response modifier in that it is available in a purely mitogenic L4 isolectin form that is stable; previously studied extensively; applicable as a simple skin test to assess immune competence and guide therapy; broadly immunostimulating with respect to both activation and proliferation of effector cell pathways; amenable to targeting maneuvers; stimulative of endogenous cytokine production; conveniently administrable by multiple routes; applicable to both active and adoptive immunotherapies; rapidly interacting irreversibly with lymphocytes; readily applied as a vaccine adjuvant; apparently nonsensitizing; relatively nontoxic, with maximum effective levels well below those for major toxicity; free from stress induction; nononcogenic; noninfectious; related to other mitogenic lectins that have augmenting therapeutic potential; compatible with other therapeutic modalities and conductive to collaborative use of other BRMs; well-suited to application as a surgical adjuvant and for prophylaxis against malignancies or infections in susceptible individuals; applicative to debilitated, immunosuppressed, and myelosuppressed patients; probably compatible with pregnancy; and potentially cost-effective.

Adjuvants, Immunologic↗
PubMed1990

Therapeutic activities of PHA-L4, the mitogenic isolectin of phytohemagglutinin.

Evidence is presented that suggests that PHA-L4 may exert the therapeutic effects of a theoretical ideal biological response modifier through its ability to do the following: to assist remission induction in certain malignancies, to exhibit direct antitumor cytotoxic effects, to enhance antineoplastic effect of radiation and chemotherapy, to decrease the liability to malignant transformation, to promote differentiation and restore normal growth responses in neoplastic cells, to manifest minimal liability to suppressor activity that would inhibit tumor rejection or antitumor cytotoxicity, to repress graft rejection and graft-versus-host responses and amplify the immunosuppressive effects of other agents in allograft transplantations, to display a direct protective effect against damage from radiation and chemotherapy, to stimulate normal myelopoiesis, to reinforce responses against various infections, to amplify tumor immunogenicity, and to attract mononuclear cells to sites of injection or local application.

Adjuvants, Immunologic↗
PubMed1990

Potential therapeutic applications of PHA-L4, the mitogenic isolectin of phytohemagglutinin.

Assuming that the attributes of the mitogenic-leukoaggglutinating (L4) isolectin of phytohemagglutinin as a proposed ideal biologic response modifier can be confirmed, it could prove to be a highly versatile agent with broad therapeutic potential for several areas of management including cancer and cancer surgery adjuvant, critical infections (including that with the human immunodeficiency viruses), vaccine adjuvant, allograft transplantations, aplastic anemias, and extensive burns. The isolectin is predictably more likely to be effective as an adjuvant or adjunctive agent than as an induction agent. Initial evaluation in dogs would serve the double purpose of establishing a presumptive key role in veterinary medicine and expediting the development of its use in humans.

Animals↗
PubMed1989

The ideal biological response modifier.

The current focus on interleukin-2 typifies the transition in cancer immunotherapy from nonspecific immunostimulants that are broadly supportive to highly defined cytokines with greater stress on treatment. With the introduction of lymphokine-activated killer cells, there was a parallel shift in emphasis from the use of allogeneic adoptive lymphocytes to in vitro expanded autologous cells. On the assumption that there should be a place for a more complete biological response modifier (BRM) applicable as a fundamental agent that would provide maximum support for all treatment modalities and that might facilitate the adoptive use of incompatible mononuclear cells when needed, an attempt was made to draw on the extensive experience with the large number of BRMs that have been studied to define the characteristics and therapeutic activities of an agent that would be ideally suited. It is ironic that the mitogenic lectins have tended to be overlooked in BRM classifications, but compelling evidence suggests that PHA-L4, the L4 isolectin of phytohemagglutinin, might at least partially fulfill all of the criteria of an ideal BRM.

Adjuvants, Immunologic↗
PubMed1978

Morphology and physiology of the McLeod erythrocyte. I. Scanning electron microscopy and electrolyte and water transport properties.

The McLeod phenotype is a rare condition characterized by deficiencies in the Kell blood group antigens of erythrocytes. The present study has defined some of the morphological and physiological characteristics of these red cells. Scanning electron microscopy reveals that approximately 27% of McLeod cells are morphologically abnormal. These aberrant forms resemble the acanthocytes of abetalipoproteinemia. Incubation experiments indicate that the morphology of McLeod erythrocytes is not due to a plasma factor. Biochemical studies reveal that the lipid composition and microviscosity of these erythrocytes are normal. In addition, isotopic tracer experiments indicate that electrolyte transport is also within the normal range. However, osmotic water permeability is approximately 30% below normal. The absence of a lipid abnormality and other experimental data suggest that the abnormal morphology and reduced H2O permeability of the McLeod erythrocyte may be due to defective membrane protein.

Biological Transport, Active↗
PubMed1977

Haematological changes associated with the McLeod phenotype of the Kell blood group system.

The McLeod phenotype is inherited as an X-linked characteristic. The red cells have weak antigenicity in the Kell blood group and lack Kx, a precursor-like substance that appears to be necessary for proper biosynthesis of Kell antigens. Kx antigen is also required for establishment of normal cell morphology. Absence of Kx antigen causes a membrane abnormality, in which the most prominent feature is acanthocytosis, and a compensated haemolytic state. The X-linked gene that determines normal Kx production is called X1k. Inheritance of a variant allele at the Xk locus is responsible for lack of Kx synthesis and the McLeod phenotype. The Xk locus is inactivated by the Lyon effect, and female carriers of the variant gene exhibit blood group mosaicism in the Kell system and have a dual red cell population of acanthocytes and discocytes.

Acanthocytes↗
PubMed1977

Erythrocyte morphology in genetic defects of the Rh and Kell blood group systems.

Absence of KX antigen and of normal expression of the Kell system antigens is associated with bizarre red blood cell morphology when observed by either light or scanning electron microscopy. Numerous acanthocytes and dacryocytes have been observed in the peripheral blood smear of an apparently healthy individual with McLeod-phenotype blood, in a male patient with type II chronic granulomatous disease who had a shortened 51Cr red blood cell survival time, and in a minor population of the red blood cells of his carrier mother.

Blood Group Antigens↗